row_id,Paragraph_ID,Paragraph,Gold Annotation
0,P100P1,Approximately 4–25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy.,"[{'e1': 'Approximately 4–25% of patients with early prostate cancer ', 'e2': 'disease recurrence ', 'relation': 'develop ', 'condition': 'following radical prostatectomy.'}]"
1,P100P13,"Consistent with the molecular subgroup representing metastatic biology, the assay was better at predicting metastatic recurrence rather than biochemical recurrence. The latter does not necessarily predict metastatic development; only one-third of patients with biochemical recurrence develop measurable metastatic disease 8 years after resection. In addition, the hazard ratio of 3.20 for metastatic recurrence compares favourably to the reported hazard ratios for other prognostic assays to predict metastatic disease, with hazard ratios ranging between 1.40 and 3.30. A significant feature of assay performance was independence from CAPRA-S, allowing the development of a combined risk model with superior performance to either CAPRA-S or the metastatic assay individually.","[{'e1': 'only one-third of patients with biochemical recurrence ', 'e2': 'measurable metastatic disease ', 'relation': 'develop ', 'condition': '8 years after resection'}]"
2,P100P7,The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population.,"[{'e1': 'The metastatic assay', 'e2': 'the ability to detect patients at risk of metastatic recurrence ', 'relation': ' may improve ', 'condition': 'following radical prostatectomy.'}]"
3,P101P11,"Our in silico functional analysis further identified a striking association of FAM13C positivity with multiple chromosomal deletions, particularly in ERG negative cancers. That these associations were markedly reduced in ERG positive cancers may be explained by the fact that the markedly higher FAM13C expression levels in ERG positive than in ERG negative cancers makes it more difficult to see further differences in expression under the selected experimental conditions. This was most obviously the case for PTEN but also seen for 5q and 6q. That FAM13C up regulation is linked to a higher prevalence of all these deletions suggests a possible impact of FAM13C on mechanisms regulating genomic integrity. In addition, the particularly strong and ERG-independent association with PTEN deletions argues for a functional interaction between both genes. PTEN is a multifunctional lipid phosphatase that negatively regulates the phosphatidylinositol-3 kinase/AKT growth pathway but is also involved in DNA repair. It is thus tempting to speculate that FAM13C might interact with PTEN deletion both in growth regulation and maintenance of genome stability. A joint role in growth control is supported by our observation that FAM13C overexpression was linked to increased cell proliferation even in PTEN deleted cancers. However, functional analyses are required to elucidate the role of FAM13C in PTEN deleted cancers.","[{'e1': 'FAM13C positivity ', 'e2': 'multiple chromosomal deletions', 'relation': ' strikingly associated with ', 'condition': 'particularly in ERG negative cancers'}, {'e1': ' FAM13C overexpression', 'e2': 'increased cell proliferation ', 'relation': ' was linked to ', 'condition': 'in PTEN deleted cancers'}]"
4,P101P7,"The prognostic impact of FAM13C expression was independent of established prognostic features, both in preoperative and in postoperative scenarios. This highlights the potential applicability of FAM13C measurement either alone or in combination with other factors for a better assessment of prostate cancer aggressiveness in clinical practice. However, given the ubiquitous nature of FAM13C expression, such a potential routine test will require a diagnostic threshold for FAM13C overexpression that needs to be defined. The Gleason Grade is the strongest established prognostic parameter in prostate cancer. Based on the large cohort of prostate cancers available at our institution, we had earlier shown that Gleason Grade information can also be used as a continuous rather than a categorical variable. Both in biopsies and in prostatectomy samples, prostate cancer prognosis continuously deteriorates with increasing percentage of unfavorable Gleason pattern found in a cancer. That FAM13C expression continuously increases with the percentage of Gleason 4 fractions in our patients further emphasizes the strong link of FAM13C expression with prostate cancer aggressiveness. The lack of an unequivocal prognostic impact of FAM13C expression in subgroups defined by a comparable quantitative Gleason grade also demonstrates how difficult it is even for very good biomarkers to surpass morphological parameters of malignancy.","[{'e1': 'The prognostic impact of FAM13C expression ', 'e2': 'established prognostic features', 'relation': 'was independent of ', 'condition': ' in preoperative scenarios'}, {'e1': 'The prognostic impact of FAM13C expression ', 'e2': 'established prognostic features', 'relation': 'was independent of ', 'condition': 'in postoperative scenarios'}]"
5,P102P1,"Our work is motivated by a prostate cancer study aimed at identifying mRNA and miRNA biomarkers that are predictive of cancer recurrence after prostatectomy. It has been shown in the literature that incorporating known biological information on pathway memberships and interactions among biomarkers improves feature selection of high-dimensional biomarkers in relation to disease risk. Biological information is often represented by graphs or networks, in which biomarkers are represented by nodes and interactions among them are represented by edges; however, biological information is often not fully known. For example, the role of microRNAs (miRNAs) in regulating gene expression is not fully understood and the miRNA regulatory network is not fully established, in which case new strategies are needed for feature selection. To this end, we treat unknown biological information as missing data, different from commonly encountered missing data problems where variable values are missing. We propose a new concept of imputing unknown biological information based on observed data and define the imputed information as the novel biological information. In addition, we propose a hierarchical group penalty to encourage sparsity and feature selection at both the pathway level and the within-pathway level, which, combined with the imputation step, allows for incorporation of known and novel biological information. While it is applicable to general regression settings, we develop and investigate the proposed approach in the context of semiparametric accelerated failure time models motivated by our data example. Data application and simulation studies show that incorporation of novel biological information improves performance in risk prediction and feature selection and the proposed penalty outperforms the extensions of several existing penalties.","[{'e1': 'mRNA and miRNA biomarkers ', 'e2': 'cancer recurrence ', 'relation': 'are predictive of ', 'condition': 'after prostatectomy'}]"
6,P102P10,"During the peer-review process, an anonymous reviewer brought to the authors’ attention another paper that addresses a similar problem. The present work was developed independently and differs in several important respects. First, the other approach does not allow for hierarchical feature selection. Second, it builds on a parametric accelerated failure time model with normal errors, which is less robust than the semiparametric accelerated failure time model used here. Third, while it uses gene pathway information for inferring the miRNA regulatory network, it incorporates only the miRNA regulatory network information in variable selection for the survival outcome model, whereas the present study uses both the gene pathway information and the miRNA regulatory network information in variable selection for the survival outcome model. Lastly, the present study formalizes the concept of imputing the component of the miRNA regulatory network that is not validated, whereas the other work does not make such a distinction between putative and validated miRNA targets.","[{'e1': 'the other approach', 'e2': 'only the miRNA regulatory network information ', 'relation': 'incorporates ', 'condition': 'in variable selection for the survival outcome model'}, {'e1': 'the present study ', 'e2': 'the gene pathway information ', 'relation': 'uses ', 'condition': 'in variable selection for the survival outcome model'}, {'e1': 'the present study ', 'e2': 'the miRNA regulatory network information ', 'relation': 'uses ', 'condition': 'in variable selection for the survival outcome model'}]"
7,P102P2,"In many biomedical studies, it is of great interest to conduct feature selection of high-dimensional data such as genomic biomarkers in relation to disease risk and prognosis while also incorporating biological information on pathway memberships and interactions among biomarkers, which has been shown in previous work to improve performance in feature selection and risk prediction. Biological information is often represented by graphs or networks, in which biomarkers are represented by nodes and interactions among them are represented by edges. However, interactions among the biomarkers of interest are often not fully known, in which case new strategies are needed to identify biomarkers that are predictive of disease risk and prognosis.","[{'e1': 'biological information on pathway memberships', 'e2': 'performance ', 'relation': 'has been shown to improve ', 'condition': 'in feature selection'}, {'e1': 'interactions among biomarkers', 'e2': 'performance ', 'relation': 'has been shown to improve ', 'condition': ' in risk prediction'}]"
8,P102P3,"Our work is motivated by a recent study of genomic biomarkers in relation to risk for prostate cancer recurrence after prostatectomy. One of the important challenges in current prostate cancer research is to develop effective methods such as biomarker assays to determine whether a patient is likely to progress to aggressive, metastatic disease or have cancer recurrence following a treatment such as surgery in order to aid clinicians in deciding on the appropriate course of treatment, for example whether immediate adjuvant therapy is warranted after prostatectomy. In particular, biomarker assays that could predict progression, metastasis and recurrence for prostate cancer patients would be of great utility in aiding clinical management of this large patient population. This study includes a training set of 73 patients and an independent testing set of 40 patients with each patient undergoing radical prostatectomy after a diagnosis of prostate cancer. RNA samples were isolated from formalin-fixed paraffin-embedded radical prostatectomy specimens that were obtained from these patients. Using these RNA samples, a customized cDNA-mediated Annealing, Selection, Extension and Ligation assay was conducted to measure expression profiles of 522 prostate cancer related genes that were selected from literature and the miRNA Expression Profiling Panel designed for the DASL assay was used to determine expression of 403 human miRNAs that were present on the miRNA microarrays used for both the training data and the testing data. Four clinical variables, prostate-specific antigen levels, histological grade, tumor stage and age, as well as the long-term clinical outcome on cancer recurrence were collected for all patients. The primary goal of this study is to identify mRNA and miRNA biomarkers that are predictive of prostate cancer recurrence after prostatectomy. Earlier analyses of the data used the l1-regularized Cox proportional hazards model and identified two prediction models, one using only mRNA biomarkers and the other using both mRNA and miRNA biomarkers, for prostate cancer recurrence, which did not incorporate biological information or conduct hierarchical feature selection.","[{'e1': 'mRNA and miRNA biomarkers ', 'e2': 'prostate cancer recurrence ', 'relation': 'are predictive of ', 'condition': 'after prostatectomy'}, {'e1': 'each patient ', 'e2': 'radical prostatectomy ', 'relation': 'undergoing ', 'condition': 'after a diagnosis of prostate cancer'}]"
9,P102P5,"Biomedical researchers have made enormous strides in discovering biological functions of genes, particularly for those involved in complex diseases such as cancer; in addition, genes have been shown to function through networks or pathways. Pathway analysis, including topology-based methods and integration analysis of multi-type data sources, has received substantial interest and played a vital role in the enrichment of underlying biological knowledge. In addition, major efforts have been made to structure and store the resulting biological information on pathways or networks in multiple public or commercial databases, including the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, BioCarta, and Cell Signaling Technology Pathway. Since such prior biological information sheds important insights on regulatory relationships between genes and gene products associated with the genesis or progression of disease, it is very valuable to incorporate such information into analysis of gene expression data in relation to disease risk. More recently, noncoding RNAs, functional transcripts that do not code for proteins, have been identified as important regulators of gene expression in many eukaryotes. Of all noncoding RNAs, microRNAs are the most widely studied and characterized, and it has been suggested that miRNAs regulate more than 30% of human genes. For example, miRNAs have been shown to downregulate gene expressions in various cancers, suggesting a role for miRNAs in tumorigenesis, and they can act as both tumor suppressor genes and oncogenes. Consequently, it has been recognized that combining information on miRNAs with other types of biomarkers may improve cancer risk assessment, detection, and prognosis. However, unlike the prior-knowledge pathways for protein-coding genes such as KEGG pathways that can be readily obtained from existing databases, the scope of miRNA roles in regulating gene expression is not fully understood and the complete picture of the miRNA regulatory network is still being established. Based on specific sequence and structural features, several algorithms have been developed to predict gene sequences that are potential regulatory targets of miRNAs. However, the vast majority of these predicted targets have not been experimentally validated and may be false positives. As a result, new strategies are needed to incorporate miRNAs and their regulatory network information in modeling cancer risk and prognosis.","[{'e1': 'noncoding RNAs', 'e2': ' important regulators of gene expression ', 'relation': 'have been identified as', 'condition': 'in many eukaryotes'}, {'e1': ' functional transcripts that do not code for proteins, ', 'e2': ' important regulators of gene expression ', 'relation': 'have been identified as', 'condition': 'in many eukaryotes'}, {'e1': 'miRNAs ', 'e2': 'gene expressions ', 'relation': 'have been shown to downregulate ', 'condition': 'in various cancers'}]"
10,P103P1,"Breast cancer is the leading cause of cancer-related deaths in women due to distinct cancer subtypes associated with early recurrence and aggressive metastatic progression. High lipoprotein-associated phospholipase A2 (PLA2G7) expression has previously been associated with aggressive disease and metastasis in prostate cancer. Here, we explore the expression pattern and functional role of PLA2G7 in breast cancer. First, a bioinformatic analysis of genome-wide gene expression data from 970 breast samples was carried out to evaluate the expression pattern of PLA2G7 mRNA in breast cancer. Second, the expression profile of PLA2G7 was studied in 1042 breast cancer samples including 89 matched lymph node metastasis samples using immunohistochemistry. Third, the effect of PLA2G7 silencing on genome-wide gene expression profile was studied and validated in cultured breast cancer cells expressing PLA2G7 at high level. Last, the expression pattern of PLA2G7 mRNA was investigated in 24 nonmalignant tissue samples and 65 primary and 7 metastatic tumour samples derived from various organs using qRT-PCR. The results from clinical breast cancer samples indicated that PLA2G7 is overexpressed in a subset of breast cancer samples compared to its expression in benign breast tissue samples and that high PLA2G7 expression associated with hormone receptor negativity as well as with poor prognosis in a subset of breast cancer samples. In vitro functional studies highlighted the putative role of PLA2G7 in the regulation of epithelial-mesenchymal transition-related signalling pathways, vimentin and E-cadherin protein expression as well as cell migration in cultured breast cancer cells. Furthermore, supporting the findings in breast and prostate cancer, high PLA2G7 mRNA expression was associated with metastatic cancer in four additional organs of origin. In conclusion, our results indicate that PLA2G7 is highly expressed in a subset of metastatic and aggressive breast cancers and in metastatic samples of various tissues of origin and promotes EMT and migration in cultured breast cancer cells.","[{'e1': 'High lipoprotein-associated phospholipase A2 (PLA2G7) expression ', 'e2': 'aggressive disease ', 'relation': 'has previously been associated with ', 'condition': 'in prostate cancer'}, {'e1': 'High lipoprotein-associated phospholipase A2 (PLA2G7) expression ', 'e2': 'metastasis ', 'relation': 'has previously been associated with ', 'condition': 'in prostate cancer'}, {'e1': 'high PLA2G7 expression ', 'e2': 'hormone receptor negativity', 'relation': 'associated with ', 'condition': ' in a subset of breast cancer samples'}, {'e1': 'high PLA2G7 expression ', 'e2': ' poor prognosis', 'relation': 'associated with ', 'condition': ' in a subset of breast cancer samples'}, {'e1': ' high PLA2G7 mRNA expression ', 'e2': 'metastatic cancer', 'relation': 'was associated with ', 'condition': ' in four additional organs of origin'}, {'e1': 'PLA2G7 ', 'e2': 'EMT ', 'relation': 'promotes ', 'condition': 'in cultured breast cancer cells'}, {'e1': 'PLA2G7 ', 'e2': 'migration ', 'relation': 'promotes ', 'condition': 'in cultured breast cancer cells'}]"
11,P103P10,"In addition to regulating EMT and invasion, PLA2G7 impairment was found to inhibit EGFR expression in vitro. Although recent results from clinical trials studying the combinatorial effect of monoclonal anti-EGFR antibody cetuximab and carboplatin or cisplatin in the treatment of triple-negative breast cancer have not been successful, combining different therapies has been suggested as a necessary step to reach significant therapeutic progress. Interestingly, darapladib, a novel PLA2G7 inhibitor, has recently been under intensive research in the area of cardiovascular diseases. In addition, lipid-lowering statins are known to reduce PLA2G7 activity in plasma, atherosclerotic plaques and cultured prostate cancer cells. Thus, although the first phase III trials with darapladib did not produce much anticipated promising results in the treatment of chronic coronary heart disease, pharmacologically well-studied and well-known molecules inhibiting PLA2G7, such as darapladib and statins, could be readily translated to in vivo preclinical studies and clinical trials also in the area of oncology. Our results propose a possible beneficial effect from the combination of PLA2G7 inhibition with other therapies in advanced breast cancer.","[{'e1': 'PLA2G7 impairment', 'e2': ' EGFR expression ', 'relation': ' was found to inhibit', 'condition': 'in vitro'}, {'e1': 'lipid-lowering statins ', 'e2': 'PLA2G7 activity', 'relation': 'are known to reduce ', 'condition': ' in plasma, atherosclerotic plaques '}, {'e1': 'lipid-lowering statins ', 'e2': 'PLA2G7 activity', 'relation': 'are known to reduce ', 'condition': 'in cultured prostate cancer cells'}]"
12,P103P4,"PLA2G7, also known as lipoprotein-associated phospholipase A2 or platelet-activating factor acetyl hydrolase, is a phospholipase that hydrolyses platelet-activating factor and truncated phospholipids generated by oxidative attack. PLA2G7 was recently reported as a novel biomarker in 50% of primary and 70% of metastatic prostate cancers and associated with aggressive disease in prostate cancer. Furthermore, PLA2G7 was identified as a potential drug target especially in ERG oncogene positive prostate cancers and the alterations induced by PLA2G7 silencing highlighted the potential of PLA2G7 inhibition as an anti-proliferative, pro-apoptotic and anti-migratory therapeutic approach. Interestingly, in addition to ERG oncogene expressing prostate cancers, high PLA2G7 expression has also been proposed to play a causal role in colon tumourigenesis downstream of loss-of-function TP53 mutations and activating RAS mutations. Supporting this finding, deletion of PLA2G7 in ApcMin/1 mice has been shown to decrease both intestinal polyposis as well as colon tumourigenesis. In recent years, PLA2G7 has also been under intensive research in the area of cardiovascular diseases. High PLA2G7 amount and enzyme activity have been associated with an increased risk of cardiovascular disease, and PLA2G7 inhibitor darapladib has been studied in the prevention and treatment of coronary heart disease.","[{'e1': 'PLA2G7 ', 'e2': 'aggressive disease ', 'relation': 'was associated with ', 'condition': 'in prostate cancer'}, {'e1': 'PLA2G7 ', 'e2': 'potential drug target ', 'relation': 'was identified as a ', 'condition': 'especially in ERG oncogene positive prostate cancers'}]"
13,P103P5,"In this study, we focus on analysing the expression pattern of PLA2G7 in breast cancer and investigate the functional role of PLA2G7 in cultured breast cancer cells using genome-wide gene expression analysis, immunohistochemistry and functional assays. The results indicate a role for PLA2G7 in the regulation of metastasis-initiating EMT and cell migration, associate high PLA2G7 mRNA expression with hormone receptor negative aggressive disease and indicate that high PLA2G7 protein expression in lymph node metastases associates with unfavourable prognosis in breast cancer.","[{'e1': ' high PLA2G7 protein expression in lymph node metastases ', 'e2': 'unfavourable prognosis ', 'relation': 'associates with ', 'condition': 'in breast cancer.'}]"
14,P103P6,"Breast cancer is the most frequent cancer in women worldwide and the leading cause of cancer-related deaths in women due to distinct cancer subtypes associated with aggressive progression. Here, we evaluated the expression pattern of PLA2G7 in breast cancer and investigated the molecular processes regulated by PLA2G7 in cultured breast cancer cells.","[{'e1': ' molecular processes', 'e2': 'PLA2G7 ', 'relation': ' regulated by ', 'condition': 'in cultured breast cancer cells.'}]"
15,P103P7,"The results from three independent clinical breast cancer sample sets showed that PLA2G7 is highly expressed in hormone receptor negative breast cancers. Analysis of transcriptomic data indicated a significant association between high PLA2G7 mRNA expression and poor prognosis in primary breast cancer samples. However, the association between high PLA2G7 protein expression and unfavourable disease outcome was not seen at the protein level in samples derived from primary breast cancers. Surprisingly, when evaluating the protein expression of PLA2G7 in the lymph node metastases, high PLA2G7 protein expression was significantly associated with poor prognosis. The reason for the inconsistent results in survival analyses of primary breast cancer samples using either PLA2G7 mRNA or protein expression remain to be investigated. The qRT-PCR primers and antibody used for evaluation of PLA2G7 expression detect both of the transcripts listed in the current release of the Ensembl database. It can be hypothesised that the results may be affected by possible PLA2G7 protein secretion or the expression of PLA2G7 by stromal and inflammatory cells present in the samples. However, the association between high PLA2G7 expression and poor prognosis using samples from lymph node metastases was acquired using the protein expression of PLA2G7 only in the tumour cells, supporting the role for PLA2G7 in cancer progression. Furthermore, PLA2G7 was also highly expressed in metastatic or aggressive tumours derived from cancers of other origins, indicating a wider range of significance in cancer progression. However, although high PLA2G7 expression associates with aggressive tumours and metastasis in many tissues, the results were opposite in thyroid tissue, suggesting that the role of PLA2G7 is multifaceted and dependent on the nature of the disease and biological context.","[{'e1': ' high PLA2G7 mRNA expression ', 'e2': 'poor prognosis ', 'relation': 'significantly associated with', 'condition': 'in primary breast cancer samples'}, {'e1': 'high PLA2G7 protein expression ', 'e2': 'poor prognosis', 'relation': 'was significantly associated with ', 'condition': 'in the lymph node metastases '}, {'e1': 'high PLA2G7 expression ', 'e2': 'aggressive tumours ', 'relation': 'associates with ', 'condition': 'in many tissues'}, {'e1': 'high PLA2G7 expression ', 'e2': 'metastasis ', 'relation': 'associates with ', 'condition': 'in many tissues'}]"
16,P104P1,"Breast cancer is the leading cause of cancer-related deaths in women due to distinct cancer subtypes associated with early recurrence and aggressive metastatic progression. High lipoprotein-associated phospholipase A2 (PLA2G7) expression has previously been associated with aggressive disease and metastasis in prostate cancer. Here, we explore the expression pattern and functional role of PLA2G7 in breast cancer. First, a bioinformatic analysis of genome-wide gene expression data from 970 breast samples was carried out to evaluate the expression pattern of PLA2G7 mRNA in breast cancer. Second, the expression profile of PLA2G7 was studied in 1042 breast cancer samples including 89 matched lymph node metastasis samples using immunohistochemistry. Third, the effect of PLA2G7 silencing on genome-wide gene expression profile was studied and validated in cultured breast cancer cells expressing PLA2G7 at high level. Last, the expression pattern of PLA2G7 mRNA was investigated in 24 nonmalignant tissue samples and 65 primary and 7 metastatic tumour samples derived from various organs using qRT-PCR.","[{'e1': 'High lipoprotein-associated phospholipase A2 (PLA2G7) expression ', 'e2': 'aggressive disease ', 'relation': 'has previously been associated with ', 'condition': 'in prostate cancer'}, {'e1': 'High lipoprotein-associated phospholipase A2 (PLA2G7) expression ', 'e2': 'metastasis ', 'relation': 'has previously been associated with ', 'condition': 'in prostate cancer'}]"
17,P104P11,"In addition to regulating EMT and invasion, PLA2G7 impairment was found to inhibit EGFR expression in vitro. Although recent results from clinical trials studying the combinatorial effect of monoclonal anti-EGFR antibody cetuximab and carboplatin or cisplatin in the treatment of triple-negative breast cancer have not been successful, combining different therapies has been suggested as a necessary step to reach significant therapeutic progress. Interestingly, darapladib, a novel PLA2G7 inhibitor, has recently been under intensive research in the area of cardiovascular diseases. In addition, lipid-lowering statins are known to reduce PLA2G7 activity in plasma, atherosclerotic plaques and cultured prostate cancer cells. Thus, although the first phase III trials with darapladib did not produce much anticipated promising results in the treatment of chronic coronary heart disease, pharmacologically well-studied and well-known molecules inhibiting PLA2G7, such as darapladib and statins, could be readily translated to in vivo preclinical studies and clinical trials also in the area of oncology. Our results propose a possible beneficial effect from the combination of PLA2G7 inhibition with other therapies in advanced breast cancer.","[{'e1': ' PLA2G7 impairment ', 'e2': 'EGFR expression ', 'relation': 'was found to inhibit ', 'condition': 'in vitro'}, {'e1': 'lipid-lowering statins ', 'e2': ' PLA2G7 activity ', 'relation': 'are known to reduce', 'condition': 'in plasma, atherosclerotic plaques'}, {'e1': 'lipid-lowering statins ', 'e2': ' PLA2G7 activity ', 'relation': 'are known to reduce', 'condition': ' in cultured prostate cancer cells'}]"
18,P104P2,"The results from clinical breast cancer samples indicated that PLA2G7 is overexpressed in a subset of breast cancer samples compared to its expression in benign breast tissue samples and that high PLA2G7 expression associated with hormone receptor negativity as well as with poor prognosis in a subset of breast cancer samples. In vitro functional studies highlighted the putative role of PLA2G7 in the regulation of epithelial-mesenchymal transition-related signalling pathways, vimentin and E-cadherin protein expression as well as cell migration in cultured breast cancer cells. Furthermore, supporting the findings in breast and prostate cancer, high PLA2G7 mRNA expression was associated with metastatic cancer in four additional organs of origin. In conclusion, our results indicate that PLA2G7 is highly expressed in a subset of metastatic and aggressive breast cancers and in metastatic samples of various tissues of origin and promotes EMT and migration in cultured breast cancer cells.","[{'e1': 'high PLA2G7 expression ', 'e2': 'hormone receptor negativity', 'relation': 'associated with ', 'condition': 'in a subset of breast cancer samples'}, {'e1': 'high PLA2G7 expression ', 'e2': 'poor prognosis ', 'relation': 'associated with ', 'condition': 'in a subset of breast cancer samples'}, {'e1': 'high PLA2G7 mRNA expression', 'e2': 'metastatic cancer ', 'relation': ' was associated with ', 'condition': 'in four additional organs of origin'}, {'e1': 'PLA2G7 ', 'e2': 'EMT', 'relation': 'promotes ', 'condition': ' in cultured breast cancer cells.'}, {'e1': 'PLA2G7 ', 'e2': ' migration', 'relation': 'promotes ', 'condition': ' in cultured breast cancer cells.'}]"
19,P104P4,"EMT, a vital process during embryogenesis and tissue repair, is characterised by specific gene expression changes, reduced intercellular adhesion, gain of mesenchymal characteristics and increased cell mobility to distant locations. Loss of immotile epithelial phenotype and gain of mesenchymal properties via EMT has recently been shown to be a key metastasis-promoting step in many cancers. In addition to enabling metastasis EMT has been suggested to promote the generation and function of cancer stem cells as well as development of drug resistance. EMT is induced by multiple oncogenic events and signalling pathways and requires the expression of a variety of regulators, including members of the Twist, Snail/Slug and Zeb transcription factor families. In addition, the SOX4-EZH2 pathway has been reported as one of the master regulators of EMT in metastatic breast cancer. Two major hallmarks of EMT are the loss of expression of the epithelial cell adhesion molecule E-cadherin and gain of expression of the major mesenchymal cell cytoskeletal component vimentin. The cytoplasmic intermediate filament protein vimentin is a component of the cytoskeleton normally found in embryonic or mesenchymal cells. However, in cancer vimentin is a marker of EMT and is expressed in neoplastic epithelial cells with metastatic properties. The expression of vimentin correlates with invasiveness and poor prognosis in clinical cancer samples.","[{'e1': 'the SOX4-EZH2 pathway ', 'e2': 'one of the master regulators of EMT ', 'relation': 'has been reported as ', 'condition': 'in metastatic breast cancer'}, {'e1': 'The expression of vimentin ', 'e2': ' invasiveness ', 'relation': 'correlates with', 'condition': 'in clinical cancer samples.'}, {'e1': 'The expression of vimentin ', 'e2': 'poor prognosis ', 'relation': 'correlates with', 'condition': 'in clinical cancer samples.'}]"
20,P104P6,"In this study, we focus on analysing the expression pattern of PLA2G7 in breast cancer and investigate the functional role of PLA2G7 in cultured breast cancer cells using genome-wide gene expression analysis, immunohistochemistry and functional assays. The results indicate a role for PLA2G7 in the regulation of metastasis-enabling EMT and cell migration, associate high PLA2G7 mRNA expression with hormone receptor negative aggressive disease and indicate that high PLA2G7 protein expression in lymph node metastases associates with unfavourable prognosis in breast cancer.","[{'e1': 'high PLA2G7 protein expression in lymph node metastases ', 'e2': 'unfavourable prognosis', 'relation': 'associates with ', 'condition': ' in breast cancer.'}]"
21,P104P7,"Breast cancer is the most frequent cancer in women worldwide and the leading cause of cancer-related deaths in women due to distinct cancer subtypes associated with aggressive progression. Here, we evaluated the expression pattern of PLA2G7 in breast cancer and investigated the molecular processes regulated by PLA2G7 in cultured breast cancer cells.","[{'e1': ' molecular processes ', 'e2': 'PLA2G7 ', 'relation': 'regulated by ', 'condition': 'in cultured breast cancer cells.'}]"
22,P104P8,"The results from three independent clinical breast cancer sample sets showed that PLA2G7 is highly expressed in hormone receptor negative breast cancers. Analysis of transcriptomic data indicated a significant association between high PLA2G7 mRNA expression and poor prognosis in primary breast cancer samples. However, the association between high PLA2G7 protein expression and unfavourable disease outcome was not seen at the protein level in samples derived from primary breast cancers. Surprisingly, when evaluating the protein expression of PLA2G7 in the lymph node metastases, high PLA2G7 protein expression was significantly associated with poor prognosis. The reason for the inconsistent results in survival analyses of primary breast cancer samples using either PLA2G7 mRNA or protein expression remain to be investigated. The qRT-PCR primers and antibody used for evaluation of PLA2G7 expression detect both of the transcripts listed in the current release of the Ensembl database. It can be hypothesised that the results may be affected by possible PLA2G7 protein secretion or the expression of PLA2G7 by stromal and inflammatory cells present in the samples. However, the association between high PLA2G7 expression and poor prognosis using samples from lymph node metastases was acquired using the protein expression of PLA2G7 only in the tumour cells, supporting the role for PLA2G7 in cancer progression. Furthermore, PLA2G7 was also highly expressed in metastatic or aggressive tumours derived from cancers of other origins, indicating a wider range of significance in cancer progression. However, although high PLA2G7 expression associates with aggressive tumours and metastasis in many tissues, the results were opposite in thyroid tissue, suggesting that the role of PLA2G7 is multifaceted and dependent on the nature of the disease and biological context.","[{'e1': ' high PLA2G7 mRNA expression ', 'e2': 'poor prognosis ', 'relation': 'significantly associated with', 'condition': 'in primary breast cancer samples'}, {'e1': 'high PLA2G7 protein expression ', 'e2': 'poor prognosis', 'relation': 'was significantly associated with ', 'condition': 'in the lymph node metastases '}, {'e1': 'high PLA2G7 expression ', 'e2': 'aggressive tumours and metastasis ', 'relation': 'associates with ', 'condition': 'in many tissues'}]"
23,P105P1,"Prostate cancer is a leading cause of cancer-related mortality worldwide. Gleason score is one of the best predictors of prostate cancer aggressiveness, but additional tumor biomarkers may improve its prognostic accuracy. We developed a gene expression signature of Gleason score to enhance the prediction of prostate cancer outcomes. Elastic net was used to construct a gene expression signature by contrasting Gleason score 8–10 versus ≤6 tumors in The Cancer Genome Atlas dataset. The constructed signature was then evaluated for its ability to predict recurrence and metastatic-lethal progression in a Fred Hutchinson patient cohort. The expression signature included transcripts representing 49 genes. In the Fred Hutchinson cohort, a 25% increase in the signature was associated with a hazard ratio of 1.51 for recurrence. The signature’s area under the curve for predicting recurrence and metastatic-lethal progression was 0.68 and 0.76, respectively. Compared to a model with age at diagnosis, pathological stage and Gleason score, the gene expression signature improved the area under the curve for recurrence and metastatic-lethal progression. Higher levels of the signature were associated with increased expression of genes in cell cycle-related pathways and decreased expression of genes in androgen response, estrogen response, oxidative phosphorylation, and apoptosis. This gene expression signature based on Gleason score may improve the prediction of recurrence as well as metastatic-lethal progression in prostate cancer patients after radical prostatectomy.","[{'e1': ' a 25% increase in the signature ', 'e2': 'a hazard ratio of 1.51 for recurrence', 'relation': 'was associated with ', 'condition': ' In the Fred Hutchinson cohort'}, {'e1': 'Higher levels of the signature ', 'e2': ' increased expression of genes ', 'relation': 'were associated with', 'condition': 'in cell cycle-related pathways'}]"
24,P105P5,"In the present study, we developed an mRNA expression signature of Gleason score using The Cancer Genome Atlas data, which predicted risk of recurrence and metastatic-lethal progression when tested in an independent patient cohort under long-term follow-up. This transcript signature may improve disease prognostication after radical prostatectomy.","[{'e1': 'This transcript signature ', 'e2': 'disease prognostication', 'relation': 'may improve ', 'condition': ' after radical prostatectomy.'}]"
25,P105P7,"In addition, several previous studies have identified gene expression signatures based on Gleason score. The previous study by Bibikova et al. utilized 512 prioritized genes that were selected based on biological relevance and publicly reported lists of genes differentially expressed in prostate tumors. They constructed a 16-gene signature using genes that were significantly correlated with Gleason score, however, none of them overlaps with the 49 genes in our signature. This may be due to differences in the input gene sets, methods used to construct the signatures, and differences in the size of the training datasets. Another study by Penney et al. considered 6,100 genes to develop a 157-gene signature of Gleason score using the adapted nearest neighbor classification method. Of those 157 genes, five genes overlap with our signature: ASPN, CENPF, ESM1, GMNN, and PAGE4. Recently, the same group of investigators utilized transcriptome-wide data to generate an updated expression signature of Gleason score that included transcripts from 30 genes. Of those 30 genes, four overlap with our Gleason score signature: ANO7, ASPN, GLB1L3, and NCAPD3. Interestingly, prior evidence also suggests that three of these genes, ANO7, ASPN, and NCAPD3, play a role in prostate cancer progression. The ANO7 gene encodes a prostate-specific cytoplasmic and polytopic membrane protein, and its activity is regulated by androgen signaling. Reduced expression of the gene has been associated with high-grade prostate cancers, which is consistent with the gene transcript’s negative coefficient in our signature of Gleason score. ASPN codes for a cartilage extracellular protein, and others have shown that it is overexpressed in both primary tumors and metastatic prostate cancer; this is consistent with the positive coefficient of this gene in our signature. NCAPD3 plays critical roles in mitotic chromosome assembly and segregation, and its expression has been associated with a decreased risk of recurrence after radical prostatectomy; this is also consistent with the negative coefficient of the gene in our signature. Thus, our gene signature of Gleason score provides confirmation for four of the 30 genes included in the Penney et al. signature for Gleason score.","[{'e1': ""NCAPD3's expression "", 'e2': 'a decreased risk of recurrence ', 'relation': 'has been associated with ', 'condition': 'after radical prostatectomy'}]"
26,P105P8,"We did not prioritize the genes based on prostate cancer-related biological pathways or patient outcomes, however, our signature also includes three genes represented in the cell cycle progression score, one gene in the metastasis-based Decipher panel, one gene in the prostate cancer recurrence-based signature, and two genes in the signature for metastatic-lethal progression previously developed by our group. Our Gleason score signature provides confirmation for several of the genes involved in prostate cancer related pathways and some previously highlighted in relation to adverse patient outcomes. In particular, evidence from multiple studies now corroborates the differential expression of ANO7, ASPN, CENPE, and CENPF in more aggressive prostate cancer.","[{'e1': 'evidence from multiple studies ', 'e2': 'the differential expression of ANO7, ASPN, CENPE, and CENPF ', 'relation': 'corroborates ', 'condition': 'in more aggressive prostate cancer.'}]"
27,P106P10,"A large number of tests for radiosensitivity have been investigated over the last three decades, and some have proven their validity in multicenter prospective settings. Of the many tests developed over the years, only several SNP assays and the RILA assay have shown replicated performance in the development phase.","[{'e1': 'only several SNP assays ', 'e2': 'replicated performance ', 'relation': 'have shown ', 'condition': 'in the development phase.'}, {'e1': 'the RILA assay ', 'e2': 'replicated performance ', 'relation': 'have shown ', 'condition': 'in the development phase.'}]"
28,P106P2,"Radiotherapy (RT) is one of the leading treatment modalities in oncology, and over 50% of patients diagnosed with cancer undergo RT during their course of treatment. Although RT is primarily a local treatment, patients are exposed to a risk of toxicities in the treatment field and surrounding tissues, which may develop acutely and late. Early toxicities are defined as side effects occurring during treatment or in the first 3 months after treatment completion. Late toxicities are defined as those occurring more than 3 months following RT and could increase over time for a period of many months to years. Late toxicities often persist and can have a significant negative impact on quality of life among cancer survivors. A sequential effect between early and late toxicity is often reported.","[{'e1': ' 50% of patients diagnosed with cancer', 'e2': 'RT ', 'relation': ' undergo ', 'condition': 'during their course of treatment'}, {'e1': 'patients ', 'e2': 'a risk of toxicities ', 'relation': 'are exposed to ', 'condition': 'in the treatment field and surrounding tissues'}]"
29,P106P5,"While early toxicities might compromise treatment completion, they can usually be managed with adequate care. In contrast, late toxicities can significantly affect quality of life in survivors and may require extensive treatments to alleviate symptoms. However, acute radiation reactions are not necessarily an indicator of a predisposition for late toxicity. Therefore, there is a need to measure individual radiosensitivity and predict the risk of toxicity before treatment. Even though many external factors such as age, concomitant medications, or recent surgery impact on the risk of toxicity, the main determinant seems to be genetic factors, that is, intrinsic radiosensitivity. However, it is unlikely that intrinsic radiosensitivity is the product of a single genetic alteration, and as such, it should be regarded as a complex polygenic trait. If a link can be found between underlying genetic variation and normal tissue susceptibility to developing toxicity, then patients could benefit from genomically guided, therapeutic individualization of their treatment: early identification of patients predicted to be at high risk for radiation-induced toxicities may benefit from either RT dose reduction or hyperfractionation. Conversely, identification of patients who are at low risk of toxicity could allow for hypofractionation of the treatment plan, thereby shortening treatment time, or dose escalation, which could improve tumor control.","[{'e1': ' late toxicities ', 'e2': 'quality of life ', 'relation': 'can significantly affect ', 'condition': 'in survivors'}]"
30,P107P1,"Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20–25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents.","[{'e1': 'Identification of these underlying DNA repair defects', 'e2': 'unique treatment opportunities for patients', 'relation': ' may present ', 'condition': 'in terms of standard-of-care treatments '}, {'e1': 'Identification of these underlying DNA repair defects', 'e2': 'unique treatment opportunities for patients', 'relation': ' may present ', 'condition': 'in selected investigational agents.'}]"
31,P108P11,"Heterogeneity in Gleason scoring within multiple foci in a tumour-containing gland is a common finding. We observed extensive heterogeneity in Gleason grade groups, such that only 11% of the tumours in the resected prostates were characterised by a single grade group in all tumour-containing blocks. This is in agreement with previous studies reporting homogeneity in 10% and 9% of specimens, although these studies analysed an unknown number of samples from fewer patients using a Gleason scoring system that is no longer in use. In addition, while previous studies mainly focused on heterogeneity between individual foci, we report on intrafocal heterogeneity in grade groups on parallel sections from the same tumour area, which were detected in 41% of the 244 investigated tumour areas. We found a difference in prevalence of primary pattern 3 and 4 for foci with Gleason sum 7, resulting in both Gleason 7a and 7b classifications, which differ substantially from one another in terms of prognosis.","[{'e1': '11% of the tumours in the resected prostates ', 'e2': 'a single grade group ', 'relation': 'were characterised by ', 'condition': 'in all tumour-containing blocks'}]"
32,P108P19,"Study limitations. Based on our classification of tumour foci in tissue blocks as diploid, tetraploid or aneuploid, we found that only 14% of the total median tumour volume in the radical resections was classified as non-diploid. Classifying a tissue block as non-diploid in this way is only based on the presence of aneuploid or tetraploid nuclei in the DNA histogram, which does not indicate that all tumour cells in that tissue block were non-diploid. The actual proportion of non-diploid cell nuclei was therefore substantially less than 14% of the median tumour volume. Also, we did not attempt to use Gleason grading, DNA ploidy or PTEN expression on the many small tumour foci of area 4 mm² or less for radical prostatectomies. From other studies, we know that these are usually, but not invariably, low grade and diploid.","[{'e1': 'only 14% of the total median tumour volume ', 'e2': 'non-diploid', 'relation': 'was classified as ', 'condition': 'in the radical resections'}]"
33,P108P7,"Tumour heterogeneity in cancer is a major obstacle in clinical practice and in the search for prognostic markers. Genomic heterogeneity in prostate cancer has been documented in studies that analysed small parts of the tumour from only a few patients. There is a growing awareness that analysis of multiple samples is necessary to overcome the limiting factor of tumour heterogeneity on the discovery and validation of biomarkers. Despite this, most of these studies still rely on solely one sample. In order to more accurately model heterogeneity, we chose to analyse a high number of samples with three independent methods applied to a large cohort of patients with long follow-up.","[{'e1': 'Tumour heterogeneity ', 'e2': 'in clinical practice ', 'relation': 'is a major obstacle ', 'condition': 'in cancer'}, {'e1': 'Tumour heterogeneity ', 'e2': 'in the search for prognostic markers', 'relation': 'is a major obstacle ', 'condition': 'in cancer'}]"
34,P109P11,"From the clinical point of view, a robust biomarker should be associated with minimal “measurement noise” (= intra-patient variation), leaving the majority of the associated variation to the biological variation (= inter-patient variation). Thus, except for miRNA-125b and miRNA-21 showing intra-tumoral heterogeneity accounting for around 50% of the total variation, the investigated miRNAs showed ICC values from 63 to 76% and may represent potential biomarkers in PCa with more than 50% of the total variation attributable to inter-patient, biological variation. However, these overall findings do indicate a rather high intra-tumoral heterogeneity of miRNA-expression in this type of cancer.","[{'e1': 'the investigated miRNAs ', 'e2': 'potential biomarkers ', 'relation': 'may represent ', 'condition': 'in PCa'}]"
35,P109P16,"Considering miRNA-143 and miRNA-145 as biological replicates, and since they originate from the same transcripts, the data taken together suggest that the miRNA-143 and miRNA-145 expressions are downregulated in PCa. Mature forms of miRNA-145 and miRNA-143 levels are regulated post-transcriptionally leading to differential levels in cells and tissue. Differential processing during biogenesis and/or degradation of the two miRNAs are likely to explain such differences. In addition, the technical detection methods, like RT-qPCR, microarrays and NGS may have different specificities linked to the individual sequences of the two miRNAs. In the ISH analyses, the LNA probes are expected to detect both precursor and mature forms, which may help to explain differences in the results between the various platforms. MiRNA-145 and miRNA-143 are involved in differentiation of smooth muscle through regulation of transcription factors like myocardin and Elk-1. Interestingly decreased levels of miRNA-143 may lead to increased TNF-a expression in smooth muscle cells. Moreover smooth muscle is a prevalent stromal component of the prostate and reduced expression of miRNA-143 and miRNA-145 may be related to loss or de-differentiation of smooth muscle, possibly related to the aggressiveness of the cancer.","[{'e1': 'decreased levels of miRNA-143 ', 'e2': 'increased TNF-a expression', 'relation': 'may lead to ', 'condition': ' in smooth muscle cells'}]"
36,P109P6,"Needle biopsy GS has been confirmed to be one of the most important prognostic factors of PCa, whereas it remains a poor predictor of clinical outcome. Introducing a histological malignancy score (GS) in 1966, D. Gleason recognized the impact of heterogeneity on GS. Accordingly, he introduced the primary and secondary histologic pattern, when evaluating PCa for obtaining the GS. Moreover, discrepancy between needle biopsy GS and overall GS of radical prostatectomy specimens is a well-known issue, which may influence the clinical outcome after surgical intervention. Histological discrepancy regarding GS can be demonstrated in approximately half of patients undergoing surgery for localized PCa, with the vast majority experiencing an upgrading of GS in their surgical specimen. About 80% of prostatectomy specimens harbor more than one cancer focus that may expose different GS. In addition, the histological GS obtained in the diagnostic needle biopsy is even more critical for non-surgical options such as active surveillance, watchful waiting, or radiotherapy, where the biopsy is the only source of tumor tissue for grading. Among the possible factors contributing to this inconsistency are varying reproducibility of the GS, and most importantly, sampling error due to a limited number of needle biopsies with varying degree of cancer infiltration. Moreover, recent research has disclosed that adoption of the new International Society of Urological Pathology grades would increase the discordance between GS as scored in the needle biopsy and radical prostatectomy. Accordingly, there is an urgent need to define more reliable biomarkers in diagnostic, prognostic and predictive settings that may contribute to solving these clinical challenges.","[{'e1': 'discrepancy between needle biopsy GS and overall GS of radical prostatectomy specimens ', 'e2': ' the clinical outcome ', 'relation': 'may influence', 'condition': 'after surgical intervention'}]"
37,P111P8,"The growing importance of miR-100-5p in carcinogenesis has been realized by several groups, which have investigated the multifaceted role of this microRNA in numerous cancers. More specifically, miR-100 has been shown to regulate apoptosis and cell cycle arrest through regulating myotubularin related protein 3 in breast cancer cells. MTMR3 inhibition through miR-100 activates p27 that can either turn on apoptosis through Bax/Bcl-2 or G2/M cell cycle arrest through CDK1/Cyclin B. An analysis of human prostate cancer samples by Leite et al. revealed a global deregulation of miR-100-5p during the transition from high grade localized prostate cancer to metastasis. Loss of miR-100-5p was concurrently reported to promote prostate cancer metastasis through regulation of migration, invasion, epithelial-mesenchymal transition, and stemness of cancer cells by upregulating AGO2 expression. In sharp contrast, however, patients with higher levels of miR-100-5p were more likely to relapse following radical prostatectomy. In light of these studies, Leite et al. suggested a context-dependent role for miR-100-5p in prostate cancer, which heavily depends on the stochastic needs of a tumour cell upon therapeutic insults and nutrient availability. Oncogenic miR-100-5p can stimulate rapid proliferation by downregulating SMARCA5, BAZ2A, and THAP2 in the pRb signalling pathway. In a reversed role, miR-100-5p could potentially downregulate mTOR pathway thus reducing cell proliferation. Further, our data indicates that miR-100 is induced by androgen ablation and concordantly androgens inhibit miR-100 expression. Even though we do not explore how miR-100 expression is regulated, we can infer that miR-100-5p plays a double role in promoting hormone resistance: it is acutely upregulated upon androgen-deprivation therapy and therefore it is required for androgen-independent survival in dormant prostate cancer cells. To the contrary, in AR-negative cells, miR-100 promotes cell proliferation. In keeping with this multifaceted role, our clinical and bio-informatics data suggest that miR-100-5p inhibits the expression of several other tumor-suppressive genes, which are involved in both androgen-independent survival and proliferation.","[{'e1': 'miR-100 ', 'e2': 'apoptosis ', 'relation': 'has been shown to regulate ', 'condition': 'through regulating myotubularin related protein 3 in breast cancer cells'}, {'e1': 'miR-100 ', 'e2': 'cell cycle arrest ', 'relation': 'has been shown to regulate ', 'condition': 'through regulating myotubularin related protein 3 in breast cancer cells'}, {'e1': ' Loss of miR-100-5p ', 'e2': 'prostate cancer metastasis ', 'relation': 'was concurrently reported to promote ', 'condition': 'through regulation of migration, invasion, epithelial-mesenchymal transition, and stemness of cancer cells by upregulating AGO2 expression'}, {'e1': 'Oncogenic miR-100-5p ', 'e2': 'rapid proliferation ', 'relation': 'can stimulate ', 'condition': 'by downregulating SMARCA5, BAZ2A, and THAP2 in the pRb signalling pathway'}, {'e1': ' miR-100 ', 'e2': 'cell proliferation', 'relation': 'promotes ', 'condition': 'in AR-negative cells'}]"
38,P111P9,"Taken these results and previous publications suggest that miR-100-5p expression may play a double role in prostate cancer: it is required to maintain the dormant state of prostate cancer cells acutely exposed to androgen-deprivation therapy; however, miR-100-5p expression is also essential in retaining proliferative and tumorigenic capacity through appropriate modulation of miR-100-5p targets and can act as a novel driver and potential therapeutic target for preventing the emergence of CRPC and NEPC. As such, our investigation highlights a novel framework in identifying dormancy-associated miRNAs, and to reveal their therapeutic potential.","[{'e1': 'miR-100-5p expression ', 'e2': 'proliferative and tumorigenic capacity ', 'relation': 'is also essential in retaining ', 'condition': 'through appropriate modulation of miR-100-5p targets '}]"
39,P112P8,"The growing importance of miR-100-5p in carcinogenesis has been realized by several groups, which have investigated the multifaceted role of this microRNA in numerous cancers. More specifically, miR-100 has been shown to regulate apoptosis and cell cycle arrest through regulating myotubularin related protein 3 in breast cancer cells. MTMR3 inhibition through miR-100 activates p27 that can either turn on apoptosis through Bax/Bcl-2 or G2/M cell cycle arrest through CDK1/Cyclin B. An analysis of human prostate cancer samples by Leite et al. revealed a global deregulation of miR-100-5p during the transition from high grade localized prostate cancer to metastasis. Loss of miR-100-5p was concurrently reported to promote prostate cancer metastasis through regulation of migration, invasion, epithelial-mesenchymal transition, and stemness of cancer cells by upregulating AGO2 expression. In sharp contrast, however, patients with higher levels of miR-100-5p were more likely to relapse following radical prostatectomy. In light of these studies, Leite et al. suggested a context-dependent role for miR-100-5p in prostate cancer, which heavily depends on the stochastic needs of a tumour cell upon therapeutic insults and nutrient availability. Oncogenic miR-100-5p can stimulate rapid proliferation by downregulating SMARCA5, BAZ2A, and THAP2 in the pRb signalling pathway. In a reversed role, miR-100-5p could potentially downregulate mTOR pathway thus reducing cell proliferation. Further, our data indicates that miR-100 is induced by androgen ablation and concordantly androgens inhibit miR-100 expression. Even though we do not explore how miR-100 expression is regulated, we can infer that miR-100-5p plays a double role in promoting hormone resistance: it is acutely upregulated upon androgen-deprivation therapy and therefore it is required for androgen-independent survival in dormant prostate cancer cells. To the contrary, in AR-negative cells, miR-100 promotes cell proliferation. In keeping with this multifaceted role, our clinical and bio-informatics data suggest that miR-100-5p inhibits the expression of several other tumor-suppressive genes, which are involved in both androgen-independent survival and proliferation.","[{'e1': 'miR-100 ', 'e2': 'apoptosis ', 'relation': 'has been shown to regulate ', 'condition': 'through regulating myotubularin related protein 3 in breast cancer cells'}, {'e1': 'miR-100 ', 'e2': 'cell cycle arrest ', 'relation': 'has been shown to regulate ', 'condition': 'through regulating myotubularin related protein 3 in breast cancer cells'}, {'e1': ' Loss of miR-100-5p ', 'e2': 'prostate cancer metastasis ', 'relation': 'was concurrently reported to promote ', 'condition': 'through regulation of migration, invasion, epithelial-mesenchymal transition, and stemness of cancer cells by upregulating AGO2 expression'}, {'e1': 'Oncogenic miR-100-5p ', 'e2': 'rapid proliferation ', 'relation': 'can stimulate ', 'condition': 'by downregulating SMARCA5, BAZ2A, and THAP2 in the pRb signalling pathway'}, {'e1': ' miR-100 ', 'e2': 'cell proliferation', 'relation': 'promotes ', 'condition': 'in AR-negative cells'}]"
40,P112P9,"Taken these results and previous publications suggest that miR-100-5p expression may play a double role in prostate cancer: it is required to maintain the dormant state of prostate cancer cells acutely exposed to androgen-deprivation therapy; however, miR-100-5p expression is also essential in retaining proliferative and tumorigenic capacity through appropriate modulation of miR-100-5p targets and can act as a novel driver and potential therapeutic target for preventing the emergence of CRPC and NEPC. As such, our investigation highlights a novel framework in identifying dormancy-associated miRNAs, and to reveal their therapeutic potential.","[{'e1': 'miR-100-5p expression ', 'e2': 'proliferative ', 'relation': 'is also essential in retaining ', 'condition': 'through appropriate modulation of miR-100-5p targets '}, {'e1': 'miR-100-5p expression ', 'e2': 'tumorigenic capacity ', 'relation': 'is also essential in retaining ', 'condition': 'through appropriate modulation of miR-100-5p targets '}]"
41,P113P1,"Prostate cancer (PCa) is a leading reason of death in men and the most diagnosed malignancies in the western countries at the present time. After radical prostatectomy (RP), nearly 30% of men develop clinical recurrence with high serum prostate-specific antigen levels. An important challenge in PCa research is to identify effective predictors of tumor recurrence. The molecular alterations in microRNAs are associated with PCa initiation and progression. Several miRNA microarray studies have been conducted in recurrence PCa, but the results vary among different studies.","[{'e1': ' nearly 30% of men ', 'e2': 'clinical recurrence with high serum prostate-specific antigen levels', 'relation': 'develop ', 'condition': 'After radical prostatectomy (RP)'}]"
42,P113P11,"By meta-analysis of six published miRNA expression datasets of recurrent PCa, we identified a common signature of a total of 37 DE microRNAs including 15 overexpressed and 22 under expressed microRNA genes across at least two datasets under the significance threshold of adjusted p-value < 0.05 in recurrence compared to non-recurrence samples. The identified 37 microRNAs in this meta-analysis were discovered as DE microRNAs in at least one dataset in the prior individual analysis. Of the 37 DE miRNAs associated with biochemical recurrence after RP, all except miR-606 have been reported to be associated with cancer in general. Fifteen miRNAs have been previously linked to PCa and of those, miR-1, miR-133B, miR-449B, and miR-221 have been described as predictive markers in PCa recurrence after RP.","[{'e1': 'miR-1, miR-133B, miR-449B, and miR-221 ', 'e2': ' predictive markers ', 'relation': 'have been described as', 'condition': 'in PCa recurrence after RP.'}, {'e1': '37 DE miRNAs ', 'e2': ' biochemical recurrence ', 'relation': 'are associated with', 'condition': 'after RP'}]"
43,P113P13,"Tumor-suppressive miR-449A targets HDAC1 and induces growth arrest in PCa. It also causes Rb-dependent cell cycle arrest and senescence in PCa cells. For a previously poorly characterized miRNA, namely miR-579, no PCa related functions have been reported. MiR-579-3p is only known as a master regulator of melanoma progression and drug resistance.","[{'e1': 'Tumor-suppressive miR-449A ', 'e2': 'HDAC1 ', 'relation': 'targets ', 'condition': 'in PCa'}, {'e1': 'Tumor-suppressive miR-449A ', 'e2': 'growth arrest ', 'relation': 'induces ', 'condition': 'in PCa'}, {'e1': 'Tumor-suppressive miR-449A ', 'e2': 'Rb-dependent cell cycle arrest ', 'relation': 'causes ', 'condition': 'in PCa cells'}, {'e1': 'Tumor-suppressive miR-449A ', 'e2': 'senescence ', 'relation': 'causes ', 'condition': 'in PCa cells'}]"
44,P113P14,"Among the under expressed DE microRNAs miR-496, miR-137, miR-1, and miR-370 had the highest combined P-values across all studies.","[{'e1': ' miR-496, miR-137, miR-1, and miR-370 ', 'e2': 'highest combined P-values across all studies.', 'relation': 'had the ', 'condition': 'Among the under expressed DE microRNAs'}]"
45,P113P15,"MiR-496 is also a previously poorly characterized miRNA, which has no functions in PCa. Methylated DNA binding domain protein 2 is known as the only transcription factor of miR-496, which coordinately silences gene expression through activation of the miR-496 promoter in breast cancer cell line.","[{'e1': 'the only transcription factor of miR-496', 'e2': 'gene expression ', 'relation': 'which coordinately silences ', 'condition': 'through activation of the miR-496 promoter in breast cancer cell line.'}]"
46,P113P16,"Methylated miR-137 host gene is a promising diagnostic and or prognostic biomarker of PCa. The epigenetic silencing of miR-137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression. MiR-137 suppresses cell growth in several cancers such as ovarian, colorectal, and gastric.","[{'e1': 'The epigenetic silencing of miR-137 ', 'e2': 'androgen signaling ', 'relation': 'is an important event in promoting ', 'condition': 'during prostate carcinogenesis and progression.'}, {'e1': 'MiR-137 ', 'e2': 'cell growth ', 'relation': 'suppresses ', 'condition': 'in several cancers such as ovarian, colorectal, and gastric.'}]"
47,P113P22,"Previous studies have reported that the diminished activity of TCF3 plays a role in lymphoid malignancies, and up-regulation of it is involved in the development and progression of colorectal cancer. TCF3 is regulated by androgens and acts as a tumor promoter in PCa. Overexpression, mutations, translocation and rearrangement of MYC is related to several cancers such as breast, PCa, gastrointestinal, melanoma, and small cell lung cancer.","[{'e1': 'TCF3 ', 'e2': 'tumor promoter ', 'relation': 'acts as a ', 'condition': 'in PCa'}]"
48,P113P25,"Cyclin-dependent kinase inhibitor 1 also is known as P21 and is involved in TP53 mediated inhibition of cellular proliferation in response to DNA damage and its overexpression results in cell cycle arrest and autophagy cell death. The expression of this gene is tightly controlled by the tumor suppressor protein p53 in a human brain tumor cell line. The CDKN1A genotypes CT and TT are associated with an increased risk of advanced prostate carcinoma compared with the CC genotype. Elevated p21 levels are associated with higher Gleason score, and increased PCa recurrence.","[{'e1': 'Cyclin-dependent kinase inhibitor 1 ', 'e2': 'TP53 mediated inhibition of cellular proliferation ', 'relation': 'is involved in ', 'condition': 'in response to DNA damage and its overexpression results in cell cycle arrest and autophagy cell death'}, {'e1': 'The expression of this gene ', 'e2': 'the tumor suppressor protein p53 ', 'relation': 'is tightly controlled by ', 'condition': 'in a human brain tumor cell line'}]"
49,P113P26,"LIM and SH3 protein 1, a promoter of cell proliferation and migration, play a significant role in cancer development and progression. LASP-1 is involved in numerous biological and pathological processes. It plays an important role in the regulation of dynamic actin-based and cytoskeletal activities. LASP-1 is highly expressed in the central nervous system and contributes to the formation and progression of prostate cancer through a NF-KB pathway.","[{'e1': 'LASP-1 ', 'e2': 'formation of prostate cancer ', 'relation': 'contributes to the ', 'condition': 'through a NF-KB pathway.'}, {'e1': 'LASP-1 ', 'e2': 'progression of prostate cancer ', 'relation': 'contributes to the ', 'condition': 'through a NF-KB pathway.'}]"
50,P113P28,"RELA also known as NF-kappa-B is a ubiquitous transcription factor involved in many biological processes such as immunity, inflammation, cell growth, differentiation, tumorigenesis and apoptosis. Zinc finger protein SNAI2 is known as a transcriptional repressor that modulates both activator-dependent and basal transcription. SNAI2 regulates cell proliferation and invasiveness of metastatic PCa cell lines. Cellular tumor antigen p53 acts as a tumor suppressor in many tumor types and induces growth arrest or apoptosis depending on the physiological circumstances and cell type.","[{'e1': ' Cellular tumor antigen p53 ', 'e2': 'tumor suppressor ', 'relation': 'acts as a ', 'condition': 'in many tumor types'}]"
51,P113P3,"Meta-analysis of six miRNA datasets revealed miR-125A, miR-199A-3P, miR-28-5P, miR-301B, miR-324-5P, miR-361-5P, miR-363*, miR-449A, miR-484, miR-498, miR-579, miR-637, miR-720, miR-874 and miR-98 are commonly upregulated miRNA genes, while miR-1, miR-133A, miR-133B, miR-137, miR-221, miR-340, miR-370, miR-449B, miR-489, miR-492, miR-496, miR-541, miR-572, miR-583, miR-606, miR-624, miR-636, miR-639, miR-661, miR-760, miR-890, and miR-939 are commonly downregulated miRNA genes in recurrent PCa samples in comparison to non-recurrent PCa samples. The network-based analysis showed that some of these miRNAs have an established prognostic significance in other cancers and can be actively involved in tumor growth. Gene ontology enrichment revealed many target genes of co-deregulated miRNAs are involved in “regulation of epithelial cell proliferation” and “tissue morphogenesis”. Kyoto Encyclopedia of Genes and Genomes analysis indicated that these miRNAs regulate cancer pathways. The PPI hub proteins analysis identified CTNNB1 as the most highly ranked hub protein. Besides, common pathway analysis showed that TCF3, MAX, MYC, CYP26A1, and SREBF1 significantly interact with those DE miRNA genes. The identified genes have been known as tumor suppressors and biomarkers which are closely related to several cancer types, such as colorectal cancer, breast cancer, PCa, gastric, and hepatocellular carcinomas. Additionally, it was shown that the combination of DE miRNAs can assist in the more specific detection of the PCa and prediction of biochemical recurrence.","[{'e1': 'miR-125A, miR-199A-3P, miR-28-5P, miR-301B, miR-324-5P, miR-361-5P, miR-363*, miR-449A, miR-484, miR-498, miR-579, miR-637, miR-720, miR-874 and miR-98 ', 'e2': ' miRNA genes', 'relation': 'are commonly upregulated', 'condition': ' in recurrent PCa samples in comparison to non-recurrent PCa samples'}, {'e1': ' miR-1, miR-133A, miR-133B, miR-137, miR-221, miR-340, miR-370, miR-449B, miR-489, miR-492, miR-496, miR-541, miR-572, miR-583, miR-606, miR-624, miR-636, miR-639, miR-661, miR-760, miR-890, and miR-939 ', 'e2': 'miRNA genes', 'relation': 'are commonly downregulated ', 'condition': ' in recurrent PCa samples in comparison to non-recurrent PCa samples'}]"
52,P113P30,"In this study, we also built new miRNA diagnostic classifiers in each GEO dataset based on best subset of DE miRNAs in the meta-analysis. These classifiers predicted biochemical recurrence after RP with very high accuracy. The highest diagnostic accuracy was given for GSE55323 with 11 miRNAs.","[{'e1': 'These classifiers ', 'e2': 'biochemical recurrence ', 'relation': 'predicted ', 'condition': 'after RP'}]"
53,P113P4,We found that the identified miRNAs through meta-analysis are candidate predictive markers for recurrent PCa after radical prostatectomy.,"[{'e1': 'miRNAs through meta-analysis ', 'e2': 'recurrent PCa ', 'relation': 'are candidate predictive markers for ', 'condition': 'after radical prostatectomy.'}]"
54,P113P7,"The miR-1, miR-133b, miR-519d, and miR-647 are new biomarkers with prognostic and diagnostic value for recurrence of PCa, which have been identified through miRNA expression profiling. The miR-449b, miR-21, miR-141 and miR-221 are also known as putative prognostic or predictive markers in PCa recurrence after RP.","[{'e1': 'The miR-449b, miR-21, miR-141 and miR-221 ', 'e2': 'putative prognostic or predictive markers ', 'relation': 'are also known as ', 'condition': 'in PCa recurrence after RP.'}]"
55,P114P2,"Prostate cancer (PCa) is the second most frequent cancer in men causing each year more than 250,000 deaths worldwide. From a genomic perspective PCa is a collection of molecular subclasses. Approximately 58% of risk for prostate cancer has been estimated to be due to inherited genetic factors. Genome-wide association studies have identified more than 100 common single-nucleotide polymorphisms associated with the risk of developing PCa. Most of these variants reside in non-coding regulatory regions and may affect the transcription factors-binding affinity. Androgen receptor regulates genes expression in multiple tissues and diseases, by targeting binding elements in promoters and distant enhancers. A recent PCa whole-genome sequencing study revealed a significant correspondence between DNA breakpoints and AR-binding sites implicating an inter-play between hormone regulation and genomic events. These studies highlight an important role of androgens in the initiation and development of PCa. Indeed, at the earliest time point of clinical presentation, PCa already harbors a range of genomic lesions possibly due to DNA repair defects. We reasoned that, over a man’s lifetime, heritable variants could potentially predispose to genomic instability in the context of variable AR signaling leading to early PCa-specific somatic genomic events. To test this hypothesis, we interrogated the constellation of transcriptomic changes in benign prostate cells for clues as to how genetic variants could impact prostate cancer development through alterations in the expression of DNA repair genes and hormone-regulated genes. Here we report a link between an inherited non-coding variant and prostate cancer somatic mutations through the interrogation of large cohorts of human data and experimental support of the functional activity of the variant locus.","[{'e1': 'Androgen receptor ', 'e2': 'genes expression ', 'relation': 'regulates ', 'condition': 'in multiple tissues and diseases, by targeting binding elements in promoters and distant enhancers'}]"
56,P115P1,"The RTK/ERK signaling pathway has been implicated in prostate cancer progression. However, the genetic relevance of this pathway to aggressive prostate cancer at the SNP level remains undefined. Here we performed a SNP and gene-based association analysis of the RTK/ERK pathway with aggressive prostate cancer in a cohort comprising 956 aggressive and 347 non-aggressive cases. We identified several loci including rs3217869/CCND2 within the pathway shown to be significantly associated with aggressive prostate cancer. Our functional analysis revealed a statistically significant relationship between rs3217869 risk genotype and decreased CCND2 expression levels in a collection of 119 prostate cancer patient samples. Reduced expression of CCND2 promoted cell proliferation and its overexpression inhibited cell growth of prostate cancer. Strikingly, CCND2 downregulation was consistently observed in the advanced prostate cancer in 18 available clinical data sets with a total amount of 1,095 prostate samples. Furthermore, the lower expression levels of CCND2 markedly correlated with prostate tumor progression to high Gleason score and elevated PSA levels, and served as an independent predictor of biochemical relapse and overall survival in a large cohort of prostate cancer patients. Together, we have identified an association of genetic variants and genes in the RTK/ERK pathway with prostate cancer aggressiveness, and highlighted the potential importance of CCND2 in prostate cancer susceptibility and tumor progression to metastasis.","[{'e1': 'the lower expression levels of CCND2 ', 'e2': 'independent predictor of biochemical relapse and overall survival ', 'relation': 'served as an ', 'condition': 'in a large cohort of prostate cancer patients'}]"
57,P115P10,"PDGF-D consists of a two-domain structure with an N-terminal CUB domain, and a C-terminal PDGF/vascular endothelial growth factor domain. Activated PDGF-D binds to its cognate receptor PDGFR-β inducing the removal of CUB domain and contributing to the development and progression of diseases. PDGF-D has been revealed with the potential oncogenic activity in the development of prostate cancer. Consistently, we observed a high tendency of PDGF-D upregulation in the metastatic prostate tumors and the tumors indicating high Gleason score and PSA levels. Moreover, in metastatic prostate cancer, PDGF-D was reported to be a regulator of osteoclastic differentiation that is critical for the establishment of skeletal metastatic deposits in prostate cancer patients.","[{'e1': 'PDGF-D ', 'e2': 'regulator of osteoclastic differentiation ', 'relation': 'was reported to be a ', 'condition': 'in metastatic prostate cancer'}, {'e1': ' PDGF-D ', 'e2': 'the potential oncogenic activity ', 'relation': 'has been revealed with ', 'condition': 'in the development of prostate cancer'}]"
58,P115P4,"With a number of genes such as EGFR, PDGF, GRB2, MET and cyclin D genes (CCND1, CCND2 and CCND3) involved, the RTK/ERK pathway regulates various biological processes including cellular signal transduction and crosstalk, cell proliferation, differentiation, survival and migration in normal and cancer development. Mutations that induce abnormalities of the structures of proteins in the pathway, may lead to cell transformation and malignancy in various types of cancer. The receptor tyrosine kinases lie upstream in the pathway, transduce the signal into the cells and trigger a cascade of phosphorylation for the downstream kinases such as the mitogen-activated protein kinase cascade, including Raf, MEK and extracellular signal-regulated kinase kinases. The consecutive signal transduction may lead to the phosphorylation of target proteins inside the cell and control normal biological activities. In contrast, the imbalance during the cascade of signal transduction and the inappropriately response for susceptible environment stimulus may lead to various diseases, including cancer. Therefore, investigation on the associations of the RTK/ERK pathway with prostate cancer risk can provide new insight into the molecular mechanisms underlying the susceptibility, and development of prostate cancer at the pathway-level, and reveal novel links between the pathway genes and disease progression to advanced stage and metastasis.","[{'e1': ' the RTK/ERK pathway ', 'e2': 'various biological processes ', 'relation': 'regulates ', 'condition': 'in normal and cancer development'}, {'e1': 'Mutations that induce abnormalities of the structures of proteins in the pathway', 'e2': 'cell transformation and malignancy ', 'relation': ' may lead to ', 'condition': 'in various types of cancer'}, {'e1': 'the imbalance ', 'e2': 'various diseases, including cancer', 'relation': 'may lead to ', 'condition': 'during the cascade of signal transduction and the inappropriately response for susceptible environment stimulus'}]"
59,P115P5,"Although the potential association of the RTK/ERK pathway with prostate cancer risk has been suggested by our previous study, the genetic and functional link of the pathway to aggressive prostate cancer have not been elucidated. In this work, on the basis of the Chinese Consortium for Prostate Cancer Genetics project, we performed SNP- and gene-based prostate cancer case-only study, as well as expression quantitative trait loci, clinical correlation, and prognosis analyses. Whereas some loci and genes were defined, only one SNP (rs3217869 in CCND2) was reproducibly identified to be significantly associated with aggressive prostate cancer by multiple testing. The eQTL analysis revealed a significant association of the risk allele at rs3217869 with decreased mRNA levels of CCND2. Interestingly, we found that CCND2 is strikingly downregulated in advanced prostate tumors and its downregulation is associated with disease progression and poor prognosis in multiple independent cohorts of prostate cancer, suggesting that CCND2 is a new biomarker to distinguish aggressive disease and a potential metastatic tumor suppressor. Thus, our study not only investigated the effects of the RTK/ERK pathway on the progression of prostate cancer, but also revealed the genetic factors responsible for aggressive disease susceptibility, highlighted the potential role of CCND2 in disease progression.","[{'e1': 'downregulation of CCND2', 'e2': 'disease progression', 'relation': 'is associated with ', 'condition': 'in multiple independent cohorts of prostate cancer'}, {'e1': 'downregulation of CCND2', 'e2': ' poor prognosis ', 'relation': 'is associated with ', 'condition': 'in multiple independent cohorts of prostate cancer'}]"
60,P115P8,"As for the associated gene, rs3217892 is within CCND2, a member of D-type cyclins that are known to be responsible for G1 phase progression. There are three D-type cyclins (CCND1, CCND2 and CCND3) involved in the regulation of transition from G1 to S during the cell cycle. Despite the fact that the overexpression of CCND2 has been reported in some cancers such as gastric cancer, our analyses showed a striking downregulation of CCND2 and its association with disease progression and poor prognosis in multiple independent cohorts of prostate cancer, suggesting that CCND2 is a potential tumor suppressor in prostate carcinoma. Consistently, our results together with the previous reports showed that restoration of CCND2 expression inhibited the proliferation of prostate cancer cells, and CCND2 knockdown accelerated prostate cancer cell proliferation. This is in line with our eQTL analysis that the risk allele A at rs3217869 is significantly associated with CCND2 downregulation, indicating a potential causal role of CCND2 underlying prostate cancer susceptibility and severity. In addition, a striking downregulation of CCND2 observed in this study may be partially explained by a previous report of promoter methylation of CCND2 in prostate cancer and its association with clinicopathological features of poor prognosis.","[{'e1': 'downregulation of CCND2 ', 'e2': 'disease progression', 'relation': 'is associated with ', 'condition': 'in multiple independent cohorts of prostate cancer'}, {'e1': 'downregulation of CCND2 ', 'e2': ' poor prognosis ', 'relation': 'is associated with ', 'condition': 'in multiple independent cohorts of prostate cancer'}, {'e1': 'CCND1', 'e2': 'transition from G1 to S ', 'relation': 'is involved in the regulation of ', 'condition': 'during the cell cycle'}, {'e1': 'CCND2 ', 'e2': 'transition from G1 to S ', 'relation': 'is involved in the regulation of ', 'condition': 'during the cell cycle'}, {'e1': 'CCND3 ', 'e2': 'transition from G1 to S ', 'relation': 'is involved in the regulation of ', 'condition': 'during the cell cycle'}]"
61,P116P1,"Androgen receptor signaling reprograms cellular metabolism to support prostate cancer growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in prostate cancer progression and participates in direct transcriptional cross-talk with the androgen receptor is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR–androgen receptor transcriptional axis integral to the metabolic rewiring of prostate cancer cells. Androgens reprogram mTOR–chromatin associations in an androgen receptor-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgen-induced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant prostate cancer cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional androgen receptor. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant prostate cancer tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from androgen receptor to nuclear mTOR as being the master transcriptional regulator of metabolism in prostate cancer.","[{'e1': 'mTOR ', 'e2': 'metabolic gene programs ', 'relation': 'was capable of transcriptionally regulating ', 'condition': 'In models of castration-resistant prostate cancer cells '}, {'e1': 'mTOR ', 'e2': 'metabolic gene programs ', 'relation': 'was capable of transcriptionally regulating ', 'condition': 'in the absence of androgens'}, {'e1': 'increased mTOR nuclear localization', 'e2': 'poor prognosis', 'relation': ' is indicative of ', 'condition': ' in patients'}]"
62,P116P2,"It is now well established that androgens play a central role in the development and progression of prostate cancer. Indeed, even at the metastatic level, androgens and more precisely the androgen receptor are well known to stimulate proliferation. However, androgen deprivation therapy does not cure prostate cancer, as the disease eventually evolves to castration-resistant prostate cancer. At this stage, several molecular mechanisms have been discovered, most of them leading to androgen receptor hyperactivation. Consequently, further knowledge of downstream effectors of the androgen receptor is necessary to dissect the molecular mechanisms governing prostate cancer progression and develop novel therapeutic approaches.","[{'e1': ' the androgen receptor', 'e2': 'proliferation', 'relation': 'is known to stimulate ', 'condition': ' at the metastatic level'}]"
63,P116P3,"Reprogrammed metabolism has been recognized as a hallmark of cancer, including in prostate cancer. Metabolically, the prostate gland is unique in that epithelial prostate cells produce high levels of citrate due to a blunted mitochondrial tricarboxylic acid cycle impeded by high zinc levels. Through malignant transformation, citrate and zinc accumulation ceases, which is thought to result from restored mitochondrial function and increased lipid synthesis. In prostate cancer, androgens and their receptor have been shown to fuel cell metabolism by rewiring nutrients and altering citrate metabolism. mTOR is another critical regulator of metabolism and cancer cell growth. The classic view of mTOR action is that microenvironmental inputs channel through a single hub to influence anabolic processes. However, emerging evidence supports multiple mTOR hubs with distinct subcellular functions. Moreover, there is growing evidence that mTOR can localize to the nucleus, associate with chromatin, and directly regulate gene expression. Nonetheless, little progress has been made in investigating a potential role for nuclear mTOR in transcriptional regulation.","[{'e1': ' androgens and their receptor ', 'e2': ' cell metabolism by rewiring nutrients and altering citrate metabolism', 'relation': 'have been shown to fuel', 'condition': ' In prostate cancer'}]"
64,P116P4,"The mTOR signaling pathway is hyperactivated in prostate cancer tumors compared with benign tissues. Alterations leading to hyperactivation of mTOR and its upstream regulators are among the most frequent genomic alterations in metastatic castration-resistant prostate cancer. However, whether nuclear mTOR is directly implicated in prostate cancer progression or transcriptional cross-talk with the androgen receptor remains unknown. In this study, we demonstrate that activated androgen receptor enhances and reprograms mTOR chromatin binding and that nuclear mTOR activity is essential for androgen-mediated transcriptional reprogramming of metabolism in prostate cancer cells. We also observed a strong correlation between mTOR nuclear content and prostate cancer aggressiveness. Finally, we identified an mTOR-dependent transcriptional signature that discriminates between normal tissues, primary cancer, and metastatic disease and predicts recurrence, underscoring the biological and clinical importance of nuclear mTOR activity.","[{'e1': ' Alterations leading to hyperactivation of mTOR and its upstream regulators ', 'e2': 'the most frequent genomic alterations ', 'relation': 'are among ', 'condition': 'in metastatic castration-resistant prostate cancer'}, {'e1': 'nuclear mTOR activity ', 'e2': ' androgen-mediated transcriptional reprogramming of metabolism ', 'relation': 'is essential for', 'condition': 'in prostate cancer cells'}]"
65,P116P9,"Overall, this study uncovers a novel mechanism by which the androgen receptor drives metabolic reprogramming through modulation of nuclear mTOR function, linking two major oncogenic drivers. The mTOR transcriptional axis emerges as a dominant component of androgen signaling. This reveals an unexpected role of nuclear mTOR and supports a paradigm shift toward mTOR as a master regulator of metabolism in prostate cancer progression. The association between nuclear mTOR and disease aggressiveness suggests its potential as a biomarker and highlights the importance of developing therapies targeting its nuclear activity.","[{'e1': ' androgen receptor ', 'e2': 'metabolic reprogramming ', 'relation': 'drives ', 'condition': 'through modulation of nuclear mTOR function'}, {'e1': 'mTOR', 'e2': 'metabolism', 'relation': 'is a master regulator of ', 'condition': ' in prostate cancer progression'}]"
66,P117P1,Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression.,"[{'e1': 'Animal model experiments ', 'e2': ' DNA repair protein ERCC1 ', 'relation': 'have suggested a role of the', 'condition': 'in prostate cancer progression.'}]"
67,P117P10,"The large number of samples in this tissue microarray and the associated database with numerous molecular features allowed us to draw conclusions on the mechanistic role of ERCC1 in prostate cancer. ERCC1-mediated endonucleolytic incision and homologous recombination have been implicated in the repair of DNA interstrand crosslinks which induce a potent replication block followed by formation and repair of double strand breaks. Defective double strand break repair and faulty DNA replication are thought to be involved in the generation of chromosomal aberrations commonly seen in cancer cells. The striking association found between elevated ERCC1 expression and chromosomal deletions as well as with a positive ERG status is suggestive of a link between ERCC1 activation and presence of chromosomal damage. ERCC1 may thus represent a surrogate for genomic instability in proliferative active prostate cancer cells. This hypothesis is further supported by the continuous increase of ERCC1 levels with the number of deletions detected, suggesting high level activity of replication-associated DNA damage repair mechanisms in subsets of prostate cancer with generation of chromosomal aberration via double strand break formation and faulty repair.","[{'e1': 'ERCC1 ', 'e2': 'a surrogate for genomic instability ', 'relation': 'may represent ', 'condition': 'in proliferative active prostate cancer cells'}]"
68,P117P13,"In summary, elevated expression of ERCC1 is strongly linked to unfavorable tumor phenotype and PSA recurrence in prostate cancer. In this study, an association between ERCC1 overexpression and chromosomal aberrations, including both ERG fusion and deletions, was observed. These findings suggest overexpression of ERCC1 in the context of replication-associated DNA damage repair, genomic instability and generation of structural chromosomal alterations.","[{'e1': 'elevated expression of ERCC1 ', 'e2': 'unfavorable tumor phenotype and PSA recurrence ', 'relation': 'is strongly linked to ', 'condition': 'in prostate cancer'}]"
69,P117P6,"The DNA repair endonuclease ERCC1 catalyzes 5′ incision during nucleotide excision repair process. ERCC1 has been described to be physiologically expressed in several tissues including skin, breast, intestine, testis, and ovary. Overexpression of ERCC1 has been found in many cancer types such as urothelial carcinoma, head and neck squamous cell carcinoma, and non-small cell lung cancer. For these entities it has been proposed that ERCC1 overexpression may serve as a prognostic and/or predictive tumor marker.","[{'e1': 'ERCC1 ', 'e2': 'physiologically expressed ', 'relation': 'has been described to be ', 'condition': 'in several tissues including skin, breast, intestine, testis, and ovary'}]"
70,P117P7,"ERCC1 is of potential interest in prostate cancer. Experimental data from a mouse model system suggested an altered ERCC1 function as potential driver for an invasive prostate cancer phenotype. Moreover, a specific nucleotide polymorphism of the ERCC1 gene was linked to prostate cancer aggressiveness in a Spanish cohort study of 494 men. The present study evaluates the clinical impact of ERCC1 expression in human prostate cancer. For this purpose, a preexisting prostate cancer tissue microarray was examined for ERCC1 expression by immunohistochemistry.","[{'e1': 'a specific nucleotide polymorphism of the ERCC1 gene ', 'e2': 'prostate cancer aggressiveness ', 'relation': 'was linked to ', 'condition': 'in a Spanish cohort study of 494 men'}]"
71,P117P8,"In this study increased expression of the DNA repair factor ERCC1 was identified as a strong prognostic marker in prostate cancer, in particular for low-grade tumors. Under the selected experimental conditions, detectable ERCC1 staining was found in 65% of prostate tumors. ERCC1 expression was virtually not detected in normal prostate epithelium. This finding suggests an upregulation of ERCC1 during tumor development in a proportion of prostate cancers. So far, comprehensive studies on ERCC1 expression in clinical prostate cancer samples are lacking. However, high-level ERCC1 expression has been reported from the prostate cancer cell lines DU-145 and LNCaP. Also, the 12 prostate cancer samples included in the Human Protein Atlas showed ERCC1 staining in 83–100% of cases depending on the antibody used.","[{'e1': 'increased expression of the DNA repair factor ERCC1 ', 'e2': 'a strong prognostic marker ', 'relation': 'was identified as ', 'condition': 'in prostate cancer, in particular for low-grade tumors'}]"
72,P117P9,The strong association of elevated ERCC1 expression with adverse morphological and clinical features of prostate cancer found in this study argues for a role of ERCC1 overexpression or activation in prostate cancer progression. This assumption is supported by findings in other cancer types where associations between high ERCC1 expression levels and reduced overall survival had been found. This includes reports on non-small cell lung cancer as well as gastric and pancreatic cancers.,"[{'e1': ' high ERCC1 expression levels ', 'e2': 'reduced overall survival', 'relation': 'was associated with', 'condition': ' in other cancer types '}]"
73,P118P11,"In this study, we hypothesized that higher mutation count and copy number variation would be associated with advanced pathologic features including tumor grade and stage and survival outcomes among patients with genitourinary malignancies in the TCGA database.","[{'e1': 'higher mutation count', 'e2': 'advanced pathologic features including tumor grade and stage and survival outcomes ', 'relation': 'would be associated with ', 'condition': 'among patients with genitourinary malignancies in the TCGA database.'}, {'e1': ' copy number variation ', 'e2': 'advanced pathologic features including tumor grade and stage and survival outcomes ', 'relation': 'would be associated with ', 'condition': 'among patients with genitourinary malignancies in the TCGA database.'}]"
74,P118P12,"Until recently, cancer biology has been studied at the single-gene level. With the availability of large genomic data sets from the TCGA, whole-genome alterations can now be studied. We performed a comprehensive analysis of how genomic changes compare both across genitourinary cancer types and within grades and stages for each malignancy. We found a wide range for somatic mutation count and copy number variation between and within tumor types. Moreover, we found that for the majority of malignancies, higher levels of mutation count and copy number variation changes were associated with advanced pathologic features. Furthermore, the degree of genomic alteration can correlate with survival. These findings give insight into tumor biology that may have implications for prognosis and therapeutics.","[{'e1': ' higher levels of mutation count ', 'e2': 'advanced pathologic features', 'relation': 'was associated with ', 'condition': ' for the majority of malignancies'}, {'e1': 'copy number variation changes ', 'e2': 'advanced pathologic features', 'relation': 'was associated with ', 'condition': ' for the majority of malignancies'}]"
75,P118P14,It has been postulated that genetic instability is associated with poorer clinical outcomes. Genetic instability has been linked to adverse pathology and survival in cancers such as colon cancer. One theory is that mutations in genes responsible for maintaining genome integrity accelerate accumulation of additional mutations leading to cancer development. The data support the role of genetic instability in progression to higher grade or stage cancer for some genitourinary malignancies.,"[{'e1': 'Genetic instability ', 'e2': 'adverse pathology ', 'relation': 'has been linked to ', 'condition': 'in cancers such as colon cancer'}, {'e1': 'Genetic instability ', 'e2': 'survival ', 'relation': 'has been linked to ', 'condition': 'in cancers such as colon cancer'}]"
76,P118P15,"High mutation count has previously been associated with greater response to certain immunotherapies. In this study, mutation count was associated with higher tumor stage and grade in several cancers and was independently associated with survival outcomes in chromophobe renal cell carcinoma.","[{'e1': 'mutation count ', 'e2': 'higher tumor stage and grade ', 'relation': 'was associated with ', 'condition': 'in several cancers '}, {'e1': 'mutation count ', 'e2': 'survival outcomes ', 'relation': 'was independently associated with ', 'condition': 'in chromophobe renal cell carcinoma.'}]"
77,P118P16,"Global copy number variation has been associated with pathologic features in several malignancies. In this study, copy number variation was associated with higher stage and grade in multiple cancers and was independently associated with poorer survival outcomes in some tumor types.","[{'e1': 'Global copy number variation ', 'e2': ' pathologic features', 'relation': 'has been associated with', 'condition': ' in several malignancies'}, {'e1': 'copy number variation ', 'e2': 'higher stage and grade', 'relation': 'was associated with ', 'condition': ' in multiple cancers '}, {'e1': 'copy number variation ', 'e2': 'poorer survival outcomes', 'relation': ' was independently associated with ', 'condition': ' in some tumor types.'}]"
78,P118P17,"These data support the concept that greater genetic variability is correlated with higher pathologic stage in multiple malignancies. As personalized medicine advances, genomic data will increasingly complement traditional pathologic data, and frameworks already exist for integrating sequencing data into clinical practice.","[{'e1': 'greater genetic variability ', 'e2': 'higher pathologic stage ', 'relation': 'is correlated with ', 'condition': 'in multiple malignancies'}]"
79,P118P5,"Among the tumor types analyzed, bladder urothelial carcinoma had the highest mutation count, followed by adrenocortical carcinoma, papillary renal cell carcinoma, testis germ cell tumor, clear cell renal cell carcinoma, prostate adenocarcinoma, pheochromocytoma and paraganglioma, and chromophobe renal cell carcinoma. The tumor type with the highest fraction of the genome with copy number variation was chromophobe renal cell carcinoma, followed by adrenocortical carcinoma, testis germ cell tumor, bladder urothelial carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, clear cell renal cell carcinoma, and prostate adenocarcinoma. Mutation count was associated with higher tumor stage and grade in several cancers and with survival outcomes in chromophobe renal cell carcinoma. Copy number variation was associated with higher stage and grade in multiple cancers and with inferior survival outcomes in some tumor types.","[{'e1': 'Mutation count ', 'e2': 'higher tumor stage and grade ', 'relation': 'was associated with ', 'condition': 'in several cancers'}, {'e1': 'Mutation count ', 'e2': 'survival outcomes ', 'relation': 'was associated with ', 'condition': 'in chromophobe renal cell carcinoma'}, {'e1': 'Copy number variation ', 'e2': 'higher stage and grade ', 'relation': 'was associated with ', 'condition': 'in multiple cancers '}, {'e1': 'Copy number variation ', 'e2': 'inferior survival outcomes ', 'relation': 'was associated with ', 'condition': 'in some tumor types.'}]"
80,P119P10,"It was notable that membership of the DESNT cancer groups was not an independent predictor of clinical outcome in the MSKCC dataset. It is possible that the difference may simply reflect statistical variation since the size of the DESNT group in several datasets was small: MSKCC, 13%; CancerMap, 8%; Stephenson, 31%; Klein, 23%. Critically, however, when the datasets with linked clinical data were combined, DESNT membership remained an independent predictor of clinical outcome. We failed to detect systematic differences between MSKCC and other datasets used in multivariate analyses.","[{'e1': 'membership of the DESNT cancer groups ', 'e2': ' clinical outcome ', 'relation': 'was not an independent predictor of', 'condition': 'in the MSKCC dataset'}]"
81,P119P13,"Notably, we failed to find any relationship between DESNT cancers and either copy number variant signatures or DNA repair gene alterations. Assignment of cancers within the DESNT classification framework, together with the use of standard clinical indicators such as Stage, Gleason sum, and PSA, copy number variant signatures, expression biomarkers such as Prolaris, Decipher, and Oncotype DX identified in supervised analyses, and urine biomarkers, should significantly enhance the ability to identify patients whose cancers should be targeted by radical therapies, avoiding the side effects of treatment, including impotence, in men with nonaggressive disease. In future studies, we are focusing on the development of both LPD- and RF-based tests that can be used to detect DESNT cancer in biopsy tissue in a clinical setting.","[{'e1': 'LPD- and RF-based tests ', 'e2': 'DESNT cancer ', 'relation': 'can be used to detect ', 'condition': 'in biopsy tissue in a clinical setting.'}]"
82,P119P8,"Our hypothesis is that completely unsupervised classification of prostate cancer based on transcriptome data has not been successful previously because individual samples of prostate cancer can contain more than one contributing lineage and frequently have heterogeneous compositions. To test this idea, in the current study, we applied Latent Process Decomposition. Based on the latent Dirichlet allocation method, LPD assesses the structure of a dataset in the absence of knowledge of clinical outcome or biological role. In contrast to standard unsupervised clustering models such as k-means and hierarchical clustering, individual cancers are not assigned to a single cluster; instead, gene expression levels in each cancer are modelled via combinations of latent processes. We previously used LPD to confirm the presence of basal and ERBB2-overexpressing categories in breast cancer datasets, and to show that, based on blood expression profiles, patients with advanced prostate cancer can be stratified into two clinically distinct groups.","[{'e1': ' LPD ', 'e2': 'the structure of a dataset ', 'relation': 'assesses ', 'condition': 'in the absence of knowledge of clinical outcome or biological role'}]"
83,P11PR1,"Up to 30% of patients with low-risk prostate cancer (PCa) are found to have features of aggressive disease at radical prostatectomy (RP). Several predictive nomo- grams and novel genomic markers have been developed to estimate the risk of adverse pathology in men eligible for active surveillance (AS). However, oncologic risk associated with these findings remains unknown.","[{'e1': ' 30% of patients with low-risk prostate cancer (PCa) ', 'e2': 'features of aggressive disease ', 'relation': 'are found to have', 'condition': 'at radical prostatectomy (RP)'}, {'e1': 'Several predictive nomo- grams and novel genomic markers ', 'e2': 'adverse pathology', 'relation': 'to estimate the risk of ', 'condition': ' in men eligible for active surveillance (AS)'}]"
84,P11PR11,"As clinicians have grown aware of the hazards associated with overdiagnosis and overtreatment of PCa, active surveillance (AS) has emerged as a viable option for the conservative management of low-risk organ-confined disease. The D'Amico classification is the most commonly used criterion for the definition of clinical risk that includes low-risk patients with Gleason scores ≤6, clinical stage T2a or lower, and PSA level ≤10 ng/ml. Such low-risk patients who are found to have low-volume disease on biopsy are offered AS, with close monitoring and the intent of curative treatment at signs of disease progression. Preliminary data from several prospective AS series have shown promising results, with very low rates of disease-specific mortality and moderate rates of intervention in the first few years of surveillance. However, definitive conclusions are premature because of the relatively short follow-up times available even in the longest series.","[{'e1': ' low-risk patients ', 'e2': 'low-volume disease ', 'relation': 'who are found to have ', 'condition': 'on biopsy'}, {'e1': 'Preliminary data from several prospective AS series ', 'e2': 'promising results, with very low rates of disease-specific mortality ', 'relation': 'have shown ', 'condition': ' in the first few years of surveillance'}, {'e1': 'Preliminary data from several prospective AS series ', 'e2': 'promising results, with moderate rates of intervention', 'relation': 'have shown ', 'condition': ' in the first few years of surveillance'}]"
85,P11PR12,"Some investigators have cautioned against overutilizing AS, citing a moderate incidence of pathologically unfavorable disease in patients with low-risk PCa who would have been eligible for AS. Reported rates of Gleason sum upgrading range from 20% to 54% and pathologic upstaging from 6% to 26%, depending on the stringency of the inclusion criteria applied. These findings have raised concerns regarding the adequacy of current AS eligibility criteria to differentiate appropriately between candidates for conservative management and those who require definitive treatment.","[{'e1': 'Gleason sum ', 'e2': '20% to 54% ', 'relation': 'upgrading range from ', 'condition': 'depending on the stringency of the inclusion criteria applied'}]"
86,P11PR13,"After examining the incidence of Gleason score upgrading in a low-risk patient population, Kulkarni et al concluded that ''caution should be exercised in recommending nonradical therapy to individuals with a high probability of undetected high-grade disease.'' Similar conclusions were drawn by Isariyawongse et al, who found that the risk of upgrading increased with advanced age and advised that ''caution should be exercised when recommending active surveillance in older men.'' To this end, several nomograms have been constructed to predict the probability of pathologic upgrading in patients with low-risk PCa. Several novel genomic markers have been developed to predict the risk of disease recurrence and progression in patients who have undergone treatment for PCa, as well as to better estimate the presence of pathologically unfavorable disease in men eligible for AS and to recommend immediate treatment for those with increased risk of upgrading or upstaging.","[{'e1': 'caution ', 'e2': 'active surveillance ', 'relation': 'should be exercised when recommending ', 'condition': 'in older men'}, {'e1': 'Several novel genomic markers ', 'e2': 'disease recurrence and progression ', 'relation': 'have been developed to predict the risk of ', 'condition': 'in patients who have undergone treatment for PCa'}, {'e1': 'Several novel genomic markers ', 'e2': 'the presence of pathologically unfavorable disease ', 'relation': 'estimate ', 'condition': 'in men eligible for AS'}]"
87,P11PR2,To determine if the presence of adverse pathologic features at RP in patients eligible for AS is prognostic of poor oncologic outcome independent of pretreatment risk status.,"[{'e1': ' adverse pathologic features', 'e2': 'poor oncologic outcome independent of pretreatment risk status', 'relation': 'is prognostic of', 'condition': 'at RP in patients eligible for AS'}]"
88,P11PR3,"A total of 2660 patients underwent immediate RP at our institution between 1998 and 2008. Patients were stratified as low, intermediate, or high risk according to the D’Amico clinical risk criteria.","[{'e1': '2660 patients ', 'e2': 'immediate RP ', 'relation': 'underwent ', 'condition': 'at our institution between 1998 and 2008'}]"
89,P11PR7,The risk of biochemical recurrence associated with adverse patho- logic findings at prostatectomy is reduced by approximately 50% in men with clinically low-risk prostate cancer.,"[{'e1': ' risk of biochemical recurrence ', 'e2': 'adverse pathologic findings', 'relation': 'associated with ', 'condition': ' at prostatectomy'}, {'e1': 'The risk of biochemical recurrence', 'e2': 'approximately 50% ', 'relation': ' is reduced by ', 'condition': 'in men with clinically low-risk prostate cancer.'}]"
90,P11PR8,"Widespread use of prostate-specific antigen (PSA) as a primary screening tool for prostate cancer (PCa) has led to the increased detection of clinically insignificant tumors. It is estimated that up to 60% of men diagnosed by PSA screening have low-risk PCa. Such interventions carry a non-negligible risk of urinary and sexual dysfunction that can adversely affect a man’s quality of life., yet most of these men undergo invasive treatment involving surgery or radiotherapy","[{'e1': '60% of men diagnosed', 'e2': 'low-risk PCa', 'relation': ' have ', 'condition': 'by PSA screening '}]"
91,P11PR9,"It is estimated that up to 60% of men diagnosed by PSA screening have low-risk PCa, yet most of these men undergo invasive treatment involving surgery or radiotherapy.","[{'e1': '60% of men diagnosed', 'e2': 'low-risk PCa', 'relation': ' have ', 'condition': 'by PSA screening '}]"
92,P121P1,"Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes ID1, ID2, ID3 and ALDH7A1 known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes ID1, CD44, HES7 and TCF3 significantly correlate with ONC201 efficacy in over 1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.","[{'e1': 'Cancer stem cells (CSCs) ', 'e2': 'recurrence ', 'relation': 'correlate with ', 'condition': 'in clinical studies'}, {'e1': 'Cancer stem cells (CSCs) ', 'e2': 'metastasis ', 'relation': 'correlate with ', 'condition': 'in clinical studies'}, {'e1': 'Cancer stem cells (CSCs) ', 'e2': 'poor survival ', 'relation': 'correlate with ', 'condition': 'in clinical studies'}, {'e1': ' the anti-CSC effects of ONC201 ', 'e2': 'early changes in stem cell-related gene expression ', 'relation': 'involve ', 'condition': 'prior to tumor cell death induction'}, {'e1': ' basal expression of CSC-related genes ID1, CD44, HES7 and TCF3 ', 'e2': 'ONC201 efficacy ', 'relation': 'significantly correlate with ', 'condition': 'in over 1000 cancer cell lines'}]"
93,P121P2,"Several clinical studies have demonstrated the relevance of cancer stem cells (CSCs) that clearly correlate with recurrence, metastasis and poor survival in solid tumors. Recent objective responses observed in Phase I/II clinical trials of various CSC-targeted agents in a number of advanced refractory solid tumors have further established the importance of CSCs as a therapeutic target.","[{'e1': 'cancer stem cells (CSCs)', 'e2': 'recurrence', 'relation': ' correlate with ', 'condition': 'in solid tumors'}, {'e1': 'cancer stem cells (CSCs)', 'e2': 'metastasis ', 'relation': ' correlate with ', 'condition': 'in solid tumors'}, {'e1': 'cancer stem cells (CSCs)', 'e2': 'poor survival ', 'relation': ' correlate with ', 'condition': 'in solid tumors'}]"
94,P121P4,"We have previously demonstrated the anti-CSC efficacy of ONC201 in vitro using established CSC markers, sphere cultures and in vivo using limiting dilution studies in colorectal cancer. Additionally, ONC201-mediated inhibition of leukemic stem cells has been confirmed in vivo. Depletion of chemotherapy-resistant colorectal CSCs by ONC201 involves an Akt-ERK-Foxo3-DR5-TRAIL-dependent mechanism of inhibition of self-renewal and cell death induction. However, it was unclear whether ONC201 depletion of CSCs is a consequence of cell death or involves specific effects on stem-cell related genes that precede inhibition of self-renewal and cell death. In this study, we show that ONC201 specifically impacts stem cell-related transcription at time points (18 and 48 h) that precede cell death which occurs 60–72 h post treatment in solid tumor cells. These early effects on stem-cell related transcription are followed by inhibition of CSC markers and self-renewal by ONC201 at 60–72 h.","[{'e1': ' ONC201 ', 'e2': 'stem cell-related transcription', 'relation': 'specifically impacts ', 'condition': ' at time points (18 and 48 h)'}]"
95,P121P5,"ONC201 attenuates diverse CSC markers such as CD44, CD133, ABCB5, ALDH1A1, ALDH7A1, NANOG, ID1, ID2, ID3 and self-renewal signaling pathways such as Wnt, Notch and Hedgehog that drive tumor initiation, therapy resistance and metastasis across various tumor types providing an opportunity for broad-spectrum anti-CSC and anti-cancer effects. The ability to target established mechanisms of CSC chemotherapy resistance such as ABCB5 is consistent with previously demonstrated ONC201 efficacy in 5-Fluorouracil resistant colorectal CSC models. Gene expression profiles in colorectal cancer cells revealed ONC201 targets CSC genes involved in prostate cancer and glioblastoma. Accordingly, ONC201 mediated inhibition of self-renewal in solid tumors was confirmed in prostate cancer cell lines and glioblastoma patient derived cells. This study provides further evidence of the broad spectrum anti-cancer efficacy of ONC201 and serves as a rationale for the ongoing single agent Phase I/II trials of ONC201 in advanced refractory solid tumors including prostate cancer and glioblastoma. Drugs targeting differentiated bulk tumor cells alone are typically associated with early clinical responses that may or may not be durable. In contrast, CSC-targeting agents are likely to achieve delayed but durable responses. ONC201’s ability to target CSCs provides an opportunity to potentially achieve durable responses in patients with advanced therapy resistant disease, especially in high unmet need indications such as recurrent glioblastoma. Additionally, approved chemotherapies or targeted agents with anti-proliferative effects that do not target CSCs could be combined with ONC201 to provide rapid de-bulking and durable clinical benefit. These results also indicate that ONC201 could be used in the adjuvant/preventative setting for cancer recurrence and metastasis prevention.","[{'e1': ' ONC201’s ability to target CSCs ', 'e2': 'an opportunity to potentially achieve durable responses ', 'relation': 'provides ', 'condition': 'in patients with advanced therapy resistant disease'}]"
96,P121P6,"To allow clinical translation of our results, we show that CSC-related gene expression can serve as a potential biomarker of ONC201 response. To demonstrate utility as a pharmacodynamic biomarker, cells with acquired resistance to ONC201 previously generated in our lab were used. ONC201 mediated CSC inhibition occurs in sensitive but not in cancer cells with acquired resistance, as confirmed by sphere formation, gene expression and protein levels of established CSC markers. To demonstrate utility as a predictive biomarker, we used the GDSC panel of cancer cell lines. Interestingly, baseline expression of CSC-related genes including high basal Wnt signaling predicted ONC201 anti-cancer efficacy in over 1000 cancer cell lines. Thus, correlative studies testing CSC expression at the RNA and protein level using circulating tumor cells and biopsies from ongoing ONC201 clinical studies are warranted.","[{'e1': 'baseline expression of CSC-related genes ', 'e2': 'ONC201 anti-cancer efficacy', 'relation': 'predicted ', 'condition': ' in over 1000 cancer cell lines'}]"
97,P122P7,"Decisions regarding ART and SRT after RP are complex for patients and clinicians, since choices can be influenced by an individual's recurrence risk, medical comorbidities and personal preferences and values. A recent Markov decision analysis model considering length and quality of life for ART versus SRT showed that the preferred treatment strategy for an individual patient is dependent upon the specific probabilities for cancer recurrence, as defined based on a genomic risk classifier assay, as well as death from causes other than prostate cancer. Genomic predictors of prostate cancer outcomes are increasingly available for clinical use, including the Decipher genomic classifier (GC) test (GenomeDx Biosciences, San Diego, CA) that provides individual estimates of the risk of metastasis after RP and is intended to be used for decision- making regarding ART and SRT. Although the information provided by the GC test has been shown to influence the recommendations of clinicians for ART after prostatectomy, GC test results can be complex and it is not yet clear how patients and their families will incorporate the genomic- based risk estimates into treatment decisions.","[{'e1': 'the Decipher genomic classifier (GC) test ', 'e2': 'individual estimates of the risk of metastasis ', 'relation': 'provides ', 'condition': 'after RP'}, {'e1': ' the information provided by the GC test ', 'e2': 'influence the recommendations of clinicians for ART', 'relation': 'has been shown to ', 'condition': ' after prostatectomy'}]"
98,P123P3,"DNA methylation plays an important role in tumorigenesis and cancer progression. DNA hypermethylation is frequently observed in the promoter regions of tumor suppressor genes, leading to gene silencing, while genome-wide global hypomethylation events are common in human cancer, causing genomic instability. Global hypomethylation in peripheral blood leukocyte DNA has been associated with increased risk of various cancers. However, no study has evaluated the role of global leukocyte DNA methylation in the prognosis of localized PCa patients.","[{'e1': 'Global hypomethylation ', 'e2': ' increased risk of various cancers', 'relation': 'has been associated with', 'condition': 'in peripheral blood leukocyte DNA'}]"
99,P123P6,"The association between cancer risk and global DNA methylation has been investigated in both tumor tissues and peripheral blood. LINE-1 was the most commonly studied global methylation marker and has been previously shown to be hypomethylated in cancer tissues. In a systematic review of global DNA methylation in PCa compared with non-tumor prostate tissue, DNA methylation was found associated with PCa development and progression. Zhu et al. found that LINE-1 hypomethylation was associated with lung cancer prevalence, but not with prostate, colorectal or other cancers. A prior large nested case–control study used pyrosequencing to quantify DNA methylation levels at LINE-1 and Alu repetitive elements in pre-diagnostic blood samples from 694 PCa cases and 703 controls from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, and did not observe a significant association with PCa for overall LINE-1 or Alu methylation levels. A recent nested control study used the Illumina Infinium HM450K BeadChip to estimate genome-wide DNA methylation in leukocytes and did not find significant association between global DNA methylation and the risk of PCa or aggressive PCa. The current literature indicates that overall global methylation level in leukocytes may not be associated with the risk of PCa overall or aggressive PCa.","[{'e1': 'DNA methylation ', 'e2': ' PCa development and progression', 'relation': 'was found associated with', 'condition': 'In a systematic review of global DNA methylation in PCa compared with non-tumor prostate tissue'}]"
100,P123P7,"In contrast to previous studies that predominantly used LINE-1 or Alu repetitive sequences for global methylation analysis, we used relatively region-specific repetitive sequences, i.e. subtelomeric repeat D4Z4 and pericentromeric repeat NBL2. Previous studies have shown that the methylation level of tandem DNA repeats in these specific chromosome regions are different from those of LINE-1 and Alu sequences. A previous study even reported inter-locus and intra-locus heterogeneity in specific LINE-1 methylation sites among different cancers. There have been ample evidence supporting that these different repetitive sequences play distinct physiological and pathological roles through various mechanisms including methylation regulation and responses to cellular stress. It is therefore not surprising that we only found a significant association between subtelomeric repeat D4Z4 methylation and PCa prognosis. Subtelomeric regions are adjacent to telomere. Telomeres are protective structure at the chromosome ends that prevent the degradation of chromosome and unnecessary DNA repair activities and recombination. Subtelomeric regions are considered part of heterochromatic regions. The methylation changes of subtelomeric regions have been related to the development or human diseases. For example, subtelomeric DNA methylation at the end of Chr. 7q, 8q, 18p, 21q and XpYp was higher in glioma patients compared to control group. Similarly, hypermethylation of subtelomeric region of Chr.18p and 21q was found in hepatocarcinomas (HCCs) compared to their adjacent non-HCCs. The subtelomeric DNA methylation was also associated with telomere length in HCC. These observations were consistent with our finding that higher methylation of subtelomeric region D4Z4 was associated with worse prognosis of PCa patients, likely due to higher chromosome instability and weak DNA repair activity of patients with higher subtelomeric methylation.","[{'e1': 'The subtelomeric DNA methylation ', 'e2': 'telomere length ', 'relation': 'was also associated with ', 'condition': 'in HCC'}, {'e1': 'higher methylation of subtelomeric region D4Z4 ', 'e2': 'worse prognosis ', 'relation': 'was associated with ', 'condition': 'of PCa patients'}]"
101,P123P8,"The major strength of this study is the relatively large patient population who were clinically managed at a single institution with comprehensive clinical and follow-up data. We measured the methylation of two distinct repetitive sequences. The pyrosequencing technique we applied is robust and reproducible. There are a couple of limitations. We could only evaluate the association with BCR, not mortality, due to the rare death events of localized PCa patients that limited our statistical power. Therefore, it is unknown whether global methylations of these repetitive sequences are associated with PCa-specific mortality. We only measured one time methylation at diagnosis, not longitudinal changes of methylation level. A recent pilot study suggested that longitudinal changes of global methylation were associated with PCa incidence and overall cancer mortality. It would be valuable to investigate whether longitudinal changes of global methylation are associated with recurrence and prostate-specific mortality. Finally, we measured the overall methylation in mixed blood cells. Blood cell heterogeneity has been found to affect the DNA methylation measurements at specific locus. Previous studies have indicated that global DNA methylation is less likely to be affected by blood cell population as measured by pyrosequencing, but no study has specifically compared NBL2 and D4Z4 methylation level among different blood cell types. We cannot rule out that the differences in blood cell types may confound our observed association with BCR. Future study is warranted to analyze specific blood cell types.","[{'e1': 'Blood cell heterogeneity ', 'e2': 'the DNA methylation measurements ', 'relation': 'has been found to affect ', 'condition': 'at specific locus'}]"
102,P124P10,"In this study, our results showed that TRAF2 was significantly upregulated in prostate cancer. Upregulation of TRAF2 was also observed in metastatic prostate cancer compared with primary prostate cancer. In addition, TRAF2 was found to be an independent prognostic factor for predicting recurrence-free survival in patients with prostate cancer, which might be associated with the effects of TRAF2 on regulating TRAIL-induced apoptosis in prostate cancer cells via c-Flip/Caspase-8 signalling.","[{'e1': 'TRAF2 ', 'e2': 'an independent prognostic factor for predicting recurrence-free survival ', 'relation': 'was found to be ', 'condition': 'in patients with prostate cancer'}]"
103,P124P11,"The tumor necrosis factor receptor-associated factor 2 was originally identified as a signalling adaptor that bound to the cytoplasmic regions of receptors in the tumor necrosis factor receptor superfamily. It was documented that TRAF2 plays vital roles in regulating immunity response, embryonic development, and stress response. TRAF2 expression has been reported to be upregulated in breast cancer. Zhao et al. found that TRAF2 expression was upregulated in primary tumor and metastatic lymph nodes compared with normal breast tissues. Different biomarkers of prostate cancer have recently been identified. In the present study, we found that TRAF2 expression was significantly upregulated in prostate cancer. TRAF2 high expression was significantly associated with tumor stage and recurrence-free survival of prostate cancer patients. In addition, using GEO datasets, we also detected that TRAF2 expression was significantly increased in castration-resistant prostate cancer. Overall, the results of our study suggest that TRAF2 is a novel prognostic biomarker for predicting recurrence-free survival of prostate cancer patients, and might affect development and progression of prostate cancer. Considering the important roles of TRAF2 in cancers, our findings are reasonable and convincing.","[{'e1': 'TRAF2 high expression ', 'e2': 'tumor stage and recurrence-free survival ', 'relation': 'was significantly associated with ', 'condition': 'of prostate cancer patients'}, {'e1': 'TRAF2 ', 'e2': 'recurrence-free survival ', 'relation': 'is a novel prognostic biomarker for predicting ', 'condition': 'of prostate cancer patient'}]"
104,P124P12,"TRAIL is an important member of the tumor necrosis factor superfamily and plays vital roles in cancer immunosurveillance. We confirmed that TRAF2, as a valuable prognostic biomarker in prostate cancer patients, can regulate TRAIL-induced apoptosis in human prostate cancer cells. It has been documented that TRAIL affects the development and progression of cancer. The present results show that TRAF2 affects the development and progression of prostate cancer through regulating TRAIL-induced apoptosis in prostate cancer cells.","[{'e1': 'TRAF2 ', 'e2': 'TRAIL-induced apoptosis ', 'relation': 'can regulate ', 'condition': 'in human prostate cancer cells'}, {'e1': ' TRAF2 ', 'e2': 'the development and progression of prostate cancer ', 'relation': 'affects ', 'condition': 'through regulating TRAIL-induced apoptosis in prostate cancer cells.'}]"
105,P124P13,"It was reported that c-Flip/Caspase-8 signalling plays a vital role in regulating the extrinsic apoptosis pathway. Our results indicate that TRAF2 overexpression inhibits Caspase-8 activation in TRAIL-treated DU-145 cells, and TRAF2 overexpression upregulates c-Flip expression in TRAIL-treated DU-145 cells. Furthermore, TRAF2 knockdown in DU-145 cells shows consistent results. Hence, it is further confirmed that TRAF2 regulates TRAIL-induced apoptosis in TRAIL-treated human prostate cancer cells via c-Flip/Caspase-8 signalling.","[{'e1': ' TRAF2 overexpression ', 'e2': 'Caspase-8 activation ', 'relation': 'inhibits ', 'condition': 'in TRAIL-treated DU-145 cells'}, {'e1': 'TRAF2 overexpression', 'e2': 'c-Flip expression ', 'relation': ' upregulates ', 'condition': 'in TRAIL-treated DU-145 cells'}, {'e1': 'TRAF2 ', 'e2': ' TRAIL-induced apoptosis ', 'relation': 'regulates', 'condition': 'in TRAIL-treated human prostate cancer cells via c-Flip/Caspase-8 signalling.'}]"
106,P124P14,"The present study firstly shows that TRAF2 may be a valuable prognostic biomarker for predicting recurrence-free survival of prostate cancer patients, which might be associated with the effects of TRAF2 on regulating TRAIL-induced apoptosis in prostate cancer. In addition, we found that TRAF2 regulates TRAIL-induced apoptosis via c-Flip/Caspase-8 signalling in prostate cancer cells.","[{'e1': 'TRAF2 ', 'e2': ' recurrence-free survival ', 'relation': 'may be a valuable prognostic biomarker for predicting', 'condition': 'of prostate cancer patients'}, {'e1': 'TRAF2 ', 'e2': 'TRAIL-induced apoptosis ', 'relation': 'regulates ', 'condition': 'via c-Flip/Caspase-8 signalling in prostate cancer cells.'}]"
107,P124P3,"We found that TRAF2 was significantly upregulated in prostate cancer compared with normal prostate samples. In addition, compared with primary prostate cancer, TRAF2 was upregulated in metastatic prostate cancer. Furthermore, our results showed that high expression of TRAF2 was significantly associated with tumor stage of prostate cancer. TRAF2 high expression was associated with poorer recurrence-free survival in prostate cancer patients. TRAF2 was found to be a valuable independent prognostic factor for predicting recurrence-free survival. In addition, the present results indicate that TRAF2 affects TRAIL-induced apoptosis in prostate cancer DU-145 cells via regulating cleaved Caspase-8 and c-Flip expression.","[{'e1': ' TRAF2 high expression ', 'e2': 'poorer recurrence-free survival', 'relation': 'was associated with ', 'condition': ' in prostate cancer patients'}, {'e1': 'TRAF2 ', 'e2': 'a valuable independent prognostic factor ', 'relation': 'was found to be ', 'condition': 'for predicting recurrence-free survival'}, {'e1': 'TRAF2 ', 'e2': 'TRAIL-induced apoptosis ', 'relation': 'affects ', 'condition': 'in prostate cancer DU-145 cells via regulating cleaved Caspase-8 and c-Flip expression'}]"
108,P124P4,"TRAF2 could be a novel prognostic biomarker for predicting recurrence-free survival in patients with prostate cancer, which might be associated with the effects of TRAF2 in regulating TRAIL-induced apoptosis in prostate cancer cells via c-Flip/Caspase-8 signalling.","[{'e1': 'TRAF2 ', 'e2': 'recurrence-free survival ', 'relation': 'could be a novel prognostic biomarker for predicting ', 'condition': 'in patients with prostate cancer'}]"
109,P124P7,"Apoptosis, also known as programmed cell death, has been shown to be related to changes in cell morphology, including cell shrinkage, chromatin condensation, and nuclear fragmentation. Both extrinsic and intrinsic apoptosis pathways were extensively studied in past years. The intrinsic apoptosis pathway is activated by intracellular signals, mainly depending on the release of proteins from mitochondria. The extrinsic apoptosis pathway is activated by extracellular ligand binding to death receptor, which causes the formation of the death-inducing signalling complex. Exogenous TRAIL is shown to induce cancer cell death without killing normal cells in humans, which makes TRAIL a potential anticancer agent. TRAIL can bind to death receptor 4 or 5, which subsequently induces activation of Caspase-8 and initiates extrinsic apoptosis. Sedger et al. reported that endogenous TRAIL can suppress tumor growth in vivo. Endogenous TRAIL secreted by natural killer cells can effectively kill cancer cells in the liver after implantation of breast and renal cancer cells. Other studies also showed that TRAIL has vital roles in regulating tumor development and metastasis. It was reported that cellular FLICE-inhibitory protein, as a protease-dead Caspase-8 homologue, can suppress the activation of Caspase-8 and thereby inhibit Caspase-8-mediated apoptosis. It has been well documented that c-Flip/Caspase-8 signalling is important in regulating activation of extrinsic apoptosis pathways. The difference in the extent of Caspase-8 activation might be associated with the cell-to-cell variation in TRAIL responsiveness. In addition, various molecules have been found to regulate TRAIL-induced apoptosis in tumor cells.","[{'e1': ' Endogenous TRAIL secreted by natural killer cells ', 'e2': 'cancer cells ', 'relation': 'can effectively kill ', 'condition': 'in the liver after implantation of breast and renal cancer cells'}, {'e1': 'various molecules ', 'e2': 'TRAIL-induced apoptosis ', 'relation': 'have been found to regulate ', 'condition': 'in tumor cells.'}]"
110,P124P8,"The tumor necrosis factor receptor-associated factor 2, also known as a signalling adaptor, belongs to the TRAF superfamily, which consists of TRAF1 to 7 in mammals. One of these functions is to serve as an adaptor protein in the assembly of receptor-associated signalling complexes and to link upstream receptors to downstream molecules. TRAF2 is an important member of these TRAFs. Zhang et al. found that TRAF2 expression was significantly increased in gastric cancer patients, which might be an independent diagnostic and prognostic indicator in gastric cancer patients. In addition, TRAF2 expression was upregulated in malignant pleural effusion cells compared with normal breast tissues. TRAF2 in malignant pleural effusion cells might be a potential prognostic factor and biomarker for predicting invasion and metastasis of breast cancer. Currently, TRAF2 expression in prostate cancer and mechanisms governing the development and progression of prostate cancer are still unknown. We speculate that TRAF2 may affect growth of prostate cancer cells via regulating TRAIL-induced apoptosis.","[{'e1': ' TRAF2 ', 'e2': ' invasion and metastasis of breast cancer', 'relation': 'might be a potential prognostic factor and biomarker for predicting', 'condition': 'in malignant pleural effusion cells '}, {'e1': 'TRAF2 ', 'e2': 'growth of prostate cancer cells ', 'relation': 'may affect ', 'condition': 'via regulating TRAIL-induced apoptosis.'}]"
111,P125P10,"We have associated PCA3 with Gleason scores in large biopsy and RP cohorts from the Decipher GRID and found patients with high Gleason have lower PCA3 expression (42 - 45%). These results indicate that most patients with high Gleason would have been reported negative on diagnostic biopsy if PCA3 biomarkers was used for initial diagnosis. Moreover, in the prospective cohort from Decipher GRID (RP, biopsy) where metastatic outcome was not available, we found that low PCA3 was strongly associated with high risk Decipher scores and was a surrogate for metastasis. Additional analyses showed that genes negatively correlated with PCA3 are associated with migration pathways such as EMT. Based on expression correlation, PCAT- 14 was the top correlated genes. In a recent report, In- vitro analysis showed that low PCAT- 14 expression increased migration while overexpressing PCAT- 14 reduced cellular growth, migration, and invasion. These results suggest that patients with low PCA3 are at a significantly higher risk of developing metastasis after RP.","[{'e1': ' PCA3 ', 'e2': 'Gleason scores ', 'relation': 'is associated with', 'condition': 'in large biopsy and RP cohorts from the Decipher GRID'}, {'e1': ' low PCA3 ', 'e2': ' high risk Decipher scores', 'relation': 'was strongly associated with', 'condition': 'in the prospective cohort from Decipher GRID (RP, biopsy)'}, {'e1': 'patients with low PCA3 ', 'e2': 'metastasis ', 'relation': 'are at a significantly higher risk of developing ', 'condition': 'after RP.'}]"
112,P125P11,"Recent work proposed that targeting PCA3 may be a putative therapeutic option to inhibit PCa growth based on interfering siRNA in LNCaP and PC3 cells. These results are contradicting our observation possibly due the different nature of genomics of LNCaP cells and RP/biopsy tissues (used in this cohort) and different AR- activity in these specimens. We observed strong positive correlation between PCA3 and ABCC4, KLK2 and KLK3 that are AR target genes supporting the modulatory effect between AR and PCA3. Activated androgen receptor (AR) also strongly induces PCA3 transcription. We believe that the interaction between AR- axis induced by testosterone and PCA3 may significantly elucidate the functional impact of PCA3. Low pre- treatment free testosterone levels, are significantly associated with tumor grade and stage, with lower testosterone levels in patients with high grade PCa. Prostate cancer patients with lower circulating free testosterone levels also have poor prognosis factors and higher tumor burden prior to treatment. These findings reinforce the idea that low PCA3 levels in high grade PCa may reflect lower circulating androgen levels, leading to weaker AR activation and transcriptional activity. This suggests that PCA3 may act as a surrogate marker for serum testosterone.","[{'e1': 'Low pre- treatment free testosterone levels ', 'e2': 'tumor grade and stage', 'relation': 'are significantly associated with ', 'condition': ' in patients with high grade PCa'}, {'e1': 'Low pre- treatment free testosterone levels ', 'e2': ' lower testosterone levels', 'relation': 'are significantly associated with ', 'condition': ' in patients with high grade PCa'}]"
113,P125P14,"In conclusion, we report that high levels of PCA3 may be a poor predictor of high grade disease in the initial biopsy setting and low PCA3 expression in primary tumors may portend a poor prognosis. We observed a unique bimodal distribution for PCA3, where low levels of PCA3 were associated with high grade disease in urine, tissue biopsy, and tissue RP, and poor survival and increased rates of metastasis after RP. To our knowledge, this is the largest study characterizing the associations between PCA3 RNA from RP tissues with pathological variables at RP and clinical outcome. Results in this study suggest that sole use of PCA3 as a stand- alone marker for prostate cancer may provide false negatives for patients with higher grade disease and urologists should be warned of this limitation.","[{'e1': 'high levels of PCA3 ', 'e2': ' high grade disease ', 'relation': 'may be a poor predictor of', 'condition': 'in the initial biopsy setting'}, {'e1': ' low PCA3 expression ', 'e2': 'a poor prognosis', 'relation': 'may portend ', 'condition': ' in primary tumors'}]"
114,P125P2,"PCA3 has a bimodal distribution in both biopsy and radical prostatectomy (RP) tissues, where low PCA3 expression was significantly associated with high grade disease. PCA3 had a poor performance of predicting high grade disease in initial biopsy with 55% sensitivity and high false negative rates; 42% of high Gleason (‚â•8) samples had low PCA3. In RP, low PCA3 is associated with adverse pathological features, clinical recurrence outcome and greater probability of metastatic progression.","[{'e1': 'PCA3', 'e2': 'high grade disease ', 'relation': ' had a poor performance of predicting ', 'condition': 'in initial biopsy '}, {'e1': ' low PCA3 ', 'e2': 'adverse pathological features', 'relation': 'is associated with ', 'condition': ' In RP'}, {'e1': ' low PCA3 expression ', 'e2': 'high grade disease', 'relation': 'was significantly associated with ', 'condition': 'in both biopsy and radical prostatectomy (RP) tissues'}]"
115,P125P5,"Prostate cancer (PCa) accounts for approximately 23% of all male cancers, and 9% of all cancer deaths among men in Europe and in Northern America. Only a subset of these patients may harbor aggressive disease with potential recurrence after first- line treatment. To improve patient management, it is essential to use accurate, quantitative tools (i.e genomic biomarkers) to identify patients with aggressive disease. Several recent studies have demonstrated the utility of protein coding and non- coding genes as prognostic and diagnostic biomarkers. In particular, a number of long non- coding RNAs (IncRNAs) including Prostate cancer antigen 3 (PCA3), PCATs and SCHLAP1 have emerged as attractive diagnostic or prognostic biomarkers.","[{'e1': 'a subset of these patients ', 'e2': 'aggressive disease with potential recurrence ', 'relation': 'may harbor ', 'condition': 'after first- line treatment'}]"
116,P125P6,"PCA3 is over- expressed in 95% of prostate cancers, with up to 100- fold up- regulation compared to adjacent non- neoplastic cells. PCA3 is also over- expressed in high- grade prostatic intraepithelial neoplasia. In clinical practice, urine- based PCA3 testing has been shown to outperform the diagnostic ability of Prostate Specific Antigen (PSA) in men with a prior negative biopsy resulting in FDA approval for clinical use for this indication. Urinary PCA3 showed similar performance in initial biopsy setting. However, the diagnostic performance of PCA3 in initial biopsy setting has led to high rate of under- diagnosis of high grade disease where PCA3 had a sensitivity of 42% with a high false negative rate using a cut- off of 60. In 463 european men scheduled for repeat biopsy, 27 (21%) cancers with a Gleason score of 7- 9 would have been missed using a cut- off of 35. Similarly, PCA3 failed to predict high grade cancers with magnetic resonance imaging (MRI) suspicion score (mSS4- 5) in the initial biopsy. These studies illuminate the potential limitations of using urinary PCA3 as a diagnostic biomarker and suggest that some patients with low PCA3 may harbor aggressive disease at initial biopsy.","[{'e1': 'urine- based PCA3 testing ', 'e2': 'the diagnostic ability of Prostate Specific Antigen (PSA) ', 'relation': 'has been shown to outperform ', 'condition': 'in men with a prior negative biopsy '}]"
117,P125P8,"The clinical utility of the PCA3 has been established as an independent diagnostic biomarker to predict prostate cancer in initial and repeat biopsy setting, primarily through urine- based analyses. However, the performance of PCA3 in initial biopsy setting has been shown in several studies to be poor with high false negative rate and low sensitivity rate leading to underdiagnosis of high grade disease. Additionally, establishing the prognostic significance of the same assay has been challenging, in part due to small cohort sizes.","[{'e1': 'The clinical utility of the PCA3 ', 'e2': 'an independent diagnostic biomarker to predict prostate cancer ', 'relation': 'has been established as ', 'condition': 'in initial and repeat biopsy setting, primarily through urine- based analyses'}]"
118,P127P1,"Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3) promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR analysis of a large radical prostatectomy cohort, we found that the TFF3 promoter was significantly hypomethylated in PC compared to non-malignant prostate tissue samples with an AUC of 0.908 by receiver operating characteristics curve analysis. Moreover, significant TFF3 promoter hypomethylation as well as overexpression was found in PC samples from another large independent patient sample set analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. TFF3 promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression was significantly associated with high ERG, ETS transcription factor expression, as well as with high Gleason score, advanced pathological T-stage, and prostate-specific antigen recurrence after radical prostatectomy. There were no significant associations between TFF3 promoter methylation levels, ERG status, or prostate-specific antigen recurrence in these radical prostatectomy cohorts. In conclusion, our results demonstrated diagnostic biomarker potential of TFF3 promoter hypomethylation for PC as well as prognostic biomarker potential of TFF3 RNA expression. To the best of our knowledge, this is the most comprehensive study of TFF3 promoter methylation and transcriptional expression in PC to date.","[{'e1': 'low TFF3 expression ', 'e2': 'high ERG ', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 expression ', 'e2': 'ETS transcription factor expression', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 expression ', 'e2': ' high Gleason score', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 expression ', 'e2': 'advanced pathological T-stage', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 expression ', 'e2': 'prostate-specific antigen recurrence ', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}]"
119,P127P10,"Of note, in addition to PC samples, TFF3 was also hypomethylated in a small set of PIN samples. At present, it is not clear how men with high grade PIN should be treated, however, current recommendations suggest that men included in screening studies should undergo re-biopsy within six months after a diagnosis of multifocal high-grade PIN. Thus, it is possible that biomarkers reporting PIN as well as PC, such as TFF3 hypomethylation, may be advantageous, either alone or in combination with PC specific biomarkers.","[{'e1': 'men included in screening studies', 'e2': 're-biopsy ', 'relation': ' should undergo ', 'condition': 'within six months after a diagnosis of multifocal high-grade PIN'}]"
120,P127P11,"In the present study, TFF3 RNA levels were significantly increased in 495 PC compared to 52 benign tissue samples. Furthermore, this is the first study to demonstrate a significant association between low TFF3 RNA levels in PC samples and high pT-stage, high Gleason score, and prostate-specific antigen recurrence after radical prostatectomy. In agreement with our results, TFF3 protein was previously reported to be overexpressed in malignant compared to benign prostate tissue samples in three tissue microarray studies. Moreover, TFF3 immunoreactivity was significantly lower in high-stage than low-stage PC in one of these studies and a similar trend was observed in another study, consistent with our results. However, in contrast to our findings at the transcriptional level, none of the previous tissue microarray studies found significant associations between prostate-specific antigen recurrence after radical prostatectomy and TFF3 protein immunohistochemistry scores. Differences in the exact composition and size of radical prostatectomy cohorts used may explain these seeming discrepancies in prognostic potential for TFF3 at the transcriptional and protein expression level. In addition, median follow-up times were not reported in the tissue microarray studies, potentially compromising the interpretation of patient outcome results. The reported differences in prognostic potential of TFF3 protein immunohistochemistry scores and RNA levels for PC might also be explained by the use of different methodologies. Immunohistochemistry scores are semi-quantitative and lack dynamic range compared to RNA sequencing, which offers a quantitative digital measurement of RNA levels. Moreover, post-transcriptional regulatory mechanisms as well as secretion of TFF3 protein could make a direct comparison between TFF3 RNA and protein expression levels problematic. Lastly, we would suggest that cellular localization of TFF3 protein should be analyzed together with expression levels, as localization has been suggested to impact the association between TFF3 protein and cancer aggressiveness in breast cancer. Additional large PC patient cohorts should be analyzed for TFF3 RNA expression to further validate the prognostic value reported here for TFF3 at the transcriptional level. This should include cohorts with long clinical follow-up, to assess if TFF3 RNA levels could have independent prognostic value.","[{'e1': ' low TFF3 RNA levels in PC samples ', 'e2': 'high pT-stage', 'relation': 'is significantly associated with', 'condition': 'after radical prostatectomy'}, {'e1': ' low TFF3 RNA levels in PC samples ', 'e2': 'high Gleason score', 'relation': 'is significantly associated with', 'condition': 'after radical prostatectomy'}, {'e1': ' low TFF3 RNA levels in PC samples ', 'e2': ' prostate-specific antigen recurrence ', 'relation': 'is significantly associated with', 'condition': 'after radical prostatectomy'}]"
121,P127P15,"In conclusion, we have demonstrated highly significant and frequent cancer-specific promoter hypomethylation of TFF3 in malignant compared to non-malignant prostate tissue samples in two large independent radical prostatectomy cohorts, including a total of 789 PC and 94 non-malignant tissue samples. Furthermore, we found a significant inverse correlation between DNA methylation and RNA expression levels for TFF3, indicating epigenetic regulation of TFF3 gene activity. Moreover, low TFF3 RNA expression was significantly associated with early prostate-specific antigen recurrence after radical prostatectomy, suggesting that TFF3 RNA expression has prognostic biomarker potential for PC. This is the largest study to date investigating the promoter methylation and RNA expression of TFF3 in PC.","[{'e1': ' DNA methylation ', 'e2': 'RNA expression levels ', 'relation': 'is inversely correlated to', 'condition': 'for TFF3'}, {'e1': 'low TFF3 RNA expression ', 'e2': 'early prostate-specific antigen recurrence ', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}]"
122,P127P3,"Aberrant DNA hypermethylation of CpG island-containing gene promoters is a hallmark for PC and other malignancies, whereas non-CpG island promoters may become either hyper- or hypomethylated in cancer cells. Some of the genes affected by perturbed promoter methylation levels are potential tumor suppressors or drivers of PC, as their transcriptional expression is repressed or activated upon promoter hyper- or hypomethylation, respectively. In recent years, several candidate promoter hypermethylation markers for PC diagnosis have been identified, some of which have also shown promising prognostic potential for prediction of prostate-specific antigen recurrence after radical prostatectomy. Likewise, aberrant promoter hypomethylation has been proposed as a cancer biomarker in, for example, myelofibrosis and glioma, but it has not been extensively studied for PC.","[{'e1': 'non-CpG island promoters ', 'e2': 'either hyper- or hypomethylated ', 'relation': 'may become ', 'condition': 'in cancer cells'}]"
123,P127P4,"The Trefoil factor 3 gene has a non-CpG island promoter and encodes the TFF3 protein, also known as intestinal trefoil factor, which is part of the mammalian family of trefoil factors. TFF3 is a small secreted peptide that is present in almost all mucin-secreting tissues, but is most abundant in goblet cells of the gastrointestinal tract, where it protects the epithelial barrier by stimulation of mucosal restitution and inhibition of apoptosis. In relation to cancer, TFF3 has been proposed to function both as an oncogene and as a tumor suppressor. Thus, high TFF3 expression has been associated with favorable prognosis in ovarian cancer and with low grade in early stage breast cancer, and TFF3 seems to act as a tumor suppressor in thyroid cancer. In contrast, TFF3 protein overexpression has been linked with aggressive disease in colon, gastric, and mammary cancer. Likewise, overexpression studies in cell line models have suggested that TFF3 serves as an oncogene in advanced metastatic castration-resistant PC. However, three independent tissue microarray studies of early stage hormone-naive PC showed no significant association between TFF3 protein levels and prostate-specific antigen recurrence after radical prostatectomy. Furthermore, TFF3 protein expression has been reported to be significantly up-regulated only in the subset of PCs that are negative for the TMPRRS2-ERG gene fusion, which occurs in approximately 50% of primary PCs, potentially further complicating the possible association of TFF3 protein levels with prognosis as ERG fusion status is not clearly associated with PC outcome after radical prostatectomy.","[{'e1': 'high TFF3 expression ', 'e2': 'favorable prognosis ', 'relation': 'has been associated with ', 'condition': 'in ovarian cancer '}, {'e1': 'high TFF3 expression ', 'e2': ' low grade ', 'relation': 'has been associated with ', 'condition': 'in early stage breast cancer'}, {'e1': 'TFF3 ', 'e2': 'a tumor suppressor ', 'relation': 'seems to act as ', 'condition': 'in thyroid cancer'}, {'e1': ' TFF3 protein overexpression', 'e2': 'aggressive disease ', 'relation': ' has been linked with ', 'condition': 'in colon cancer'}, {'e1': ' TFF3 protein overexpression', 'e2': 'aggressive disease ', 'relation': ' has been linked with ', 'condition': 'in gastric cancer'}, {'e1': ' TFF3 protein overexpression', 'e2': 'aggressive disease ', 'relation': ' has been linked with ', 'condition': 'in mammary cancer'}, {'e1': 'TFF3 ', 'e2': 'an oncogene ', 'relation': 'serves as ', 'condition': 'in advanced metastatic castration-resistant PC'}]"
124,P127P5,"Although we have previously reported that the TFF3 promoter is hypomethylated in PC tissue samples, this was based only on a small patient sample set. In the same study, we showed that TFF3 promoter methylation and RNA expression levels were inversely correlated in a small set of prostate cell lines, suggesting epigenetic regulation of gene activity. However, larger patient sample sets are needed to investigate the diagnostic and prognostic biomarker potential of TFF3 promoter methylation and RNA expression in PC.","[{'e1': 'TFF3 promoter methylation ', 'e2': 'RNA expression levels ', 'relation': 'is inversely correlated with', 'condition': ' in a small set of prostate cell lines'}]"
125,P127P6,"Accordingly, in the present study, we have evaluated TFF3 promoter hypomethylation and RNA expression in multiple large PC patient cohorts. First, using quantitative methylation specific PCR analysis, we found highly frequent and cancer-specific TFF3 promoter hypomethylation in a set of 292 PC compared to 33 non-malignant prostate tissue samples. This was validated in an independent patient sample set comprising 497 PC and 50 non-malignant prostate tissue samples, analyzed on the Illumina 450K DNA methylation array. Using matched RNA sequencing data, we also found that TFF3 RNA levels were significantly upregulated in PC compared to non-malignant prostate tissue samples as well as significantly inversely correlated with promoter methylation levels, consistent with epigenetic regulation of TFF3 gene activity. Moreover, low TFF3 RNA expression was significantly associated with high ERG expression, high Gleason score, advanced pathological T-stage, and prostate-specific antigen recurrence after radical prostatectomy. In contrast, there was no significant association between TFF3 promoter methylation levels, ERG status, and prostate-specific antigen recurrence risk in these radical prostatectomy cohorts.","[{'e1': 'low TFF3 expression ', 'e2': 'high ERG expresssion', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 expression ', 'e2': ' high Gleason score', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 expression ', 'e2': 'advanced pathological T-stage', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 expression ', 'e2': 'prostate-specific antigen recurrence ', 'relation': 'was significantly associated with ', 'condition': 'after radical prostatectomy'}]"
126,P127P7,"To the best of our knowledge, this is the largest study of TFF3 promoter methylation and RNA expression in PC to date. We found that the TFF3 gene promoter was frequently hypomethylated in PC compared to non-malignant prostate tissue samples, suggesting diagnostic biomarker potential for PC. Additionally, TFF3 RNA expression levels were significantly increased in PC tissue samples and correlated inversely with TFF3 promoter methylation, consistent with epigenetic regulation of gene activity. Furthermore, low TFF3 RNA levels were significantly associated with high ERG expression, high Gleason score, advanced pT-stage, and early prostate-specific antigen recurrence after radical prostatectomy. Together, our results demonstrate diagnostic biomarker potential of TFF3 promoter hypomethylation as well as prognostic biomarker potential of TFF3 RNA expression for clinically localized PC.","[{'e1': 'low TFF3 RNA levels ', 'e2': 'high ERG expression', 'relation': 'were significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 RNA levels ', 'e2': 'high Gleason score', 'relation': 'were significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 RNA levels ', 'e2': ' advanced pT-stage ', 'relation': 'were significantly associated with ', 'condition': 'after radical prostatectomy'}, {'e1': 'low TFF3 RNA levels ', 'e2': 'early prostate-specific antigen recurrence ', 'relation': 'were significantly associated with ', 'condition': 'after radical prostatectomy'}]"
127,P128P1,"We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN−/−mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n = 300), testing (n = 185), and validation (n = 194) cohort. Using the Cox model, a nine-gene signature was derived, including eight genes from a MUC1-related network (APC, CTNNB1/β-catenin, GALNT10, GRB2, LYN, SIGLEC1, SOS1, and ZAP70) and FAM84B. Genomic alterations in these genes reduce disease-free survival (DFS) in the training (P = .00161), testing (P = .00699), entire (training + testing, P = 5.557e-5), and a validation cohort (P = 3.326e-5). The signature independently predicts PC recurrence [hazard ratio (HR) = 1.731; 95% confidence interval (CI): 1.104-2.712; P = .0167] after adjusting for known clinical factors and stratifies patients with high risk of PC recurrence using the median (HR 2.072; 95% CI: 1.245-3.450, P = .0051) and quartile 3 (HR 3.707, 95% CI: 1.949-7.052, P = 6.51e-5) scores. Several novel β-catenin mutants are identified in PCs leading to a rapid onset of death and recurrence. Genomic alterations in APC and CTNNB1/β-catenin reduce DFS in two independent PC cohorts (n = 485, P = .0369; n = 84, P = .0437). The nine-gene signature also associates with reductions in overall survival (P = .0458) and DFS (P = .0163) in melanoma patients (n = 367). MUC1 upregulation is associated with CRPC and bone metastasis. A nine-gene signature derived from a MUC1 network predicts PC recurrence.","[{'e1': ' The nine-gene signature', 'e2': 'reductions in overall survival and DFS ', 'relation': ' associates with ', 'condition': 'in melanoma patients'}]"
128,P128P2,"Prostate cancer (PC) is the most common male- specific malignancy in the developed world. The disease progresses with a heterogeneous path. A large proportion of the low- grade [Gleason score 6/WHO grade (group) I] tumors are indolent. Approximately 30% of patients after radical prostatectomy (RP) will experience a rise in serum prostate- specific antigen (PSA); this biochemical recurrence (BR) significantly increases risk of PC metastasis and the development of castration- resistant prostate cancer (CRPC). PC predominantly metastasizes to the bone; the standard treatment for this condition is androgen deprivation therapy (ADT). The treatment is palliative, and patients eventually develop CRPC. Although the recent developments have resulted in three sets of mRNA- based signatures, Oncotype DX (Genomic Prostate Score/GPS), Prolaris, and Decipher (Genomic Classifier), that evaluate the risk of PC progression, our ability to stratify PCs with high risk of progression remains poor. It is therefore critical to improve our understanding of factors contributing to PC recurrence, metastasis, and CRPC.","[{'e1': ' 30% of patients ', 'e2': 'a rise in serum prostate- specific antigen (PSA)', 'relation': 'will experience ', 'condition': 'after radical prostatectomy (RP) '}]"
129,P128P5,"MUC1 expression is commonly altered in multiple tumor types and promotes tumor progression through activation of the EGFR, β-catenin, NF-κB, PKM2, and other pathways. MUC1 thus has applications in diagnosis and therapy. However, both applications need further investigations.","[{'e1': 'MUC1 expression', 'e2': 'tumor progression ', 'relation': ' promotes ', 'condition': 'through activation of the EGFR'}, {'e1': 'MUC1 expression', 'e2': 'tumor progression ', 'relation': ' promotes ', 'condition': 'through activation of the β-catenin'}, {'e1': 'MUC1 expression', 'e2': 'tumor progression ', 'relation': ' promotes ', 'condition': 'through activation of the NF-κB'}, {'e1': 'MUC1 expression', 'e2': 'tumor progression ', 'relation': ' promotes ', 'condition': 'through activation of the PKM2'}]"
130,P128P6,"We provide the first evidence for elevations of the MUC1 proteins in CRPC (Figures 1 and 2). Of note, a recent phase II clinical trial reported that a MUC1- based dendritic cells (DC) vaccination delayed PC progression in patients with nonmetastatic CRPC. Our study provides further support for DC- MUC1 vaccine in treating CRPC.","[{'e1': ' MUC1- based dendritic cells (DC) vaccination ', 'e2': ' PC progression ', 'relation': 'delayed', 'condition': 'in patients with nonmetastatic CRPC'}]"
131,P128P8,"We further pioneered a thorough investigation of MUC1's biomarker value in the context of a network setting, an effort supported by the need of multiple factors to effectively predict cancer progression. Our nine- gene signature associates robustly with PC recurrence. Currently, there are 3 sets of mRNA- based signatures to evaluate PC progression: the 17- gene Oncotype DX (GPS), the 31- gene signature of CCP (cell cycle progression; Prolaris), and the 22- gene Decipher signature. Adding to this resource is our novel nine- gene genomic signature. Interestingly, this signature also correlates with reductions in DFS and OS in patients with cutaneous melanoma.","[{'e1': 'nine- gene genomic signature', 'e2': 'reductions in DFS and OS ', 'relation': 'correlates with ', 'condition': 'in patients with cutaneous melanoma.'}]"
132,P129P8,"Recently, driven by technological improvements and cost reductions, considerable attention has been directed towards the whole genome analysis of cancer genomes. We employed this technology to assess mechanisms of copy number gain and loss. Our study confirmed several previous observations and yielded novel features of the human prostate cancer genome, including highlighting the importance of lincRNAs in prostate cancer development. Previously, lincRNAs PCAT1 and CCAT1 were identified as targets in the 8q24.21 gain and we confirmed this and demonstrated the presence of mutations in patients with gains. PCAT1 and CCAT1 have been identified as prognostic markers in prostate and colorectal cancers acting as transcriptional regulators of the genes BRCA2 and MYC respectively. We also identified a hotspot of mutations at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci within the 16q23.1-q24.3 loss. Low FENDRR expression is associated with poor prognosis in gastric cancer. KCCAT91, CCAT1, CAT2185 and KCCAT199 were also identified as possible targets.","[{'e1': 'Low FENDRR expression ', 'e2': 'poor prognosis ', 'relation': 'is associated with ', 'condition': 'in gastric cancer'}]"
133,P12PR1,"MicroRNAs are important epigenetic regulators of protein expression by triggering degradation of target mRNAs and/or inhibiting their translation. Dysregulation of microRNA expression has been reported in several cancers, including prostate cancer (PC). We comprehensively characterized the proteomic footprint of a panel of 12 microRNAs that are potently suppressed in metastatic PC (SiM-miRNAs: miR-1, miR-133a, miR-133b, miR-135a, miR-143-3p, miR-145-3p, miR-205, miR-221-3p, miR-221-5p, miR-222-3p, miR-24-1-5p, and miR-31) using reverse-phase proteomic arrays. Re-expression of these SiM-miRNAs in PC cells suppressed cell proliferation and targeted key oncogenic pathways, including cell cycle, apoptosis, Akt/mammalian target of rapamycin signaling, metastasis and the androgen receptor (AR) axis. However, only 12%, at most, of these observed protein expression changes could be explained by predicted direct binding of miRNAs to corresponding mRNAs, suggesting that the majority of these proteomic effects result indirectly. AR and its steroid receptor coactivators (SRCs; SRC-1, -2 and -3) were recurrently affected by these SiM miRNAs. In agreement, we identified inverse correlations between expression of these SiM-miRNAs and early clinical recurrence, as well as with AR transcriptional activity in human PC tissues. We also identified robust induction of miR-135a by androgen and strong direct binding of AR to the miR-135a locus. As miR-135a potently suppresses AR expression, this results in a negative feedback loop that suppresses AR protein expression in an androgen-dependent manner, while de-repressing AR expression upon androgen deprivation. Our results demonstrate that epigenetic silencing of these SiM-miRNAs can result in increased AR axis activity and cell proliferation, thus contributing to disease progression. We further demonstrate that a negative feedback loop involving miR-135a can restore AR expression under androgen-deprivation conditions, thus contributing to the upregulation of AR protein expression in castration-resistant PC. Finally, our unbiased proteomic profiling demonstrates that the majority of actual protein expression changes induced by SiM-miRNAs cannot be explained based on predicted direct interactions.","[{'e1': 'MicroRNAs ', 'e2': 'protein expression ', 'relation': 'are important epigenetic regulators of ', 'condition': 'by triggering degradation of target mRNAs '}, {'e1': 'MicroRNAs ', 'e2': 'protein expression ', 'relation': 'are important epigenetic regulators of ', 'condition': 'by inhibiting their translation'}, {'e1': ' expression of these SiM-miRNAs ', 'e2': 'early clinical recurrence', 'relation': ' inverse correlation with', 'condition': 'in human PC tissues'}, {'e1': ' expression of these SiM-miRNAs ', 'e2': 'AR transcriptional activity in human PC tissues', 'relation': ' inverse correlation with', 'condition': 'in human PC tissues'}, {'e1': 'negative feedback loop ', 'e2': ' AR protein expression', 'relation': 'that suppresses', 'condition': ' in an androgen-dependent manner'}, {'e1': 'negative feedback loop ', 'e2': 'upregulation of AR protein expression ', 'relation': 'contributes to the ', 'condition': 'in castration-resistant PC.'}]"
134,P12PR11,"Therefore, epigenetic silencing appears to be a widespread phenomenon that suppresses the expression of SiM-miRNAs in metPC, which, in turn, results in diverse impact across cellular functions, including increased AR activity, mitosis, AKT/mTOR signaling, epithelial-to-mesenchymal transition and metastatic potential, while suppressing apoptosis and cell adhesion. As previously proposed for miR-31, these findings further support that epigenetic therapies could complement existing hormonal agents in order to inhibit the AR axis in CRPC.","[{'e1': 'epigenetic silencing appears to be a widespread phenomenon ', 'e2': ' expression of SiM-miRNAs ', 'relation': 'that suppresses the', 'condition': 'in metPC'}, {'e1': 'epigenetic therapies', 'e2': 'existing hormonal agents in order to inhibit the AR axis ', 'relation': ' could complement ', 'condition': 'in CRPC.'}]"
135,P12PR3,"miRNAs bind preferentially to specific sequences in the 3′-untranslated region (3′UTR) of mRNAs and regulate protein output through translational repression and/or mRNA destabilization. Most protein-coding genes and virtually every biological process are subject to miRNA-mediated regulation. Several studies have examined the dysregulated expression of miRNAs in PC (mainly in primary tumors) and have reported suppression of several miRNAs, including miR-31, miR-1, miR-133a/b, miR-143 and miR-145, with variable overlap in their findings. Conversely, several miRs have been found to be overexpressed in PC, including miR-32, miR-148a, miR-21 and the miR-106b-25 cluster.","[{'e1': 'miRNAs ', 'e2': ' specific sequences', 'relation': 'bind preferentially to', 'condition': ' in the 3′-untranslated region (3′UTR) of mRNAs'}, {'e1': 'miRNAs ', 'e2': 'protein output', 'relation': ' regulate ', 'condition': ' through translational repression '}, {'e1': 'miRNAs ', 'e2': 'protein output', 'relation': ' regulate ', 'condition': ' through mRNA destabilization'}, {'e1': 'Several studies ', 'e2': 'dysregulated expression of miRNAs', 'relation': 'have examined the ', 'condition': ' in PC (mainly in primary tumors'}]"
136,P12PR4,"Although the expression patterns of miRNAs in PC (in particular primary tumors) have been reported extensively, their targets are not well defined and usually limited to the study of a handful of selected proteins and/or guided by bioinformatic predictions of miRNA/mRNA interactions using algorithms that frequently give incomplete or divergent results and can miss important effects. Consequently, a comprehensive map of the actual (not predicted) proteomic footprint of miRNAs in PC, in particular metastatic PC (metPC), is still needed. Utilizing reverse phase proteomic arrays (RPPA), we characterized the proteomic footprint of miRNAs that are suppressed in metPC (SiM-miRNAs). We determined that the majority of the proteomic effects observed result from indirect mechanism(s), whereas only 12% of the protein alterations could be explained by direct binding of miRNAs to the corresponding mRNA. AR itself and its SRC-1, -2 and -3 were observed to be recurrently affected by these SiM-miRNAs. We also identified a negative feedback loop involving miR-135a 5p that regulates AR protein expression by androgen and de-represses AR expression upon androgen deprivation, thus contributing to the upregulation of AR protein expression in CRPC.","[{'e1': 'a negative feedback loop', 'e2': 'miR-135a 5p that regulates AR protein expression ', 'relation': ' involving ', 'condition': 'by androgen'}, {'e1': 'a negative feedback loop', 'e2': ' AR expression ', 'relation': 'de-represses', 'condition': 'upon androgen deprivation'}, {'e1': 'a negative feedback loop', 'e2': ' upregulation of AR protein expression', 'relation': ' contributes to the', 'condition': ' in CRPC'}]"
137,P12PR6,"As the proteomic footprint of microRNAs in PC had not previously been defined comprehensively, we performed RPPA analysis in LNCaP cells transfected with SiM-miRNA mimetics. Importantly, only 12%, at most, of the SiM-miRNA effects measured via RPPA could be explained by direct miRNA binding onto the corresponding mRNAs. This suggests that most of the effects of these SiM-mRNAs in cells are indirect. We focused our analysis on common pathways concordantly regulated by the SiM miRNAs in metPC, including cell cycle, apoptosis, Akt/mTOR signaling, migration and the AR axis. In agreement with the antiproliferative effect of the SiM-miRNAs seen in our MTT experiments, positive regulators of cell cycle, including phospho Rb(pSer807/811), cyclin B1, PCNA, CDK1 and c-Myc, were suppressed, whereas the negative regulators Cyclin E1 and p27 were increased. The increase in p27 was consistent with the significant decrease in Skp2. Receptor tyrosine kinase cell cycle activators, such as HER3, pEGFR(pTyr1068), IGF1R and VEGFR2, as well as the AKT/mTOR pathway were frequently affected. Positive regulators of apoptosis, such as BIM and SMAC, were increased, in agreement with our finding of increased cleaved PARP levels. Moreover, cell junction and cell adhesion proteins that generally suppress cell migration and metastasis, such as claudin7 and E-cadherin, were concordantly upregulated upon re-expression of the SiM-miRNAs mimetics. MicroRNA-205 has been previously reported to upregulate E-cadherin and induce a mesenchymal-to-epithelial transition. Collectively, our findings indicate that the SiM-miRNAs induce a combinatorial proteomic profile of suppressed cell cycle, AKT/mTOR signaling and metastatic potential, with increased apoptosis, cell adhesion and mesenchymal-to-epithelial transition signaling. Thus the silencing of these miRNAs in metPC would have a broad impact across cellular functions, including increased mitosis, AKT/mTOR signaling and metastatic potential, while suppressing apoptosis and cell adhesion.","[{'e1': 'common pathways ', 'e2': 'the SiM miRNAs ', 'relation': 'concordantly regulated by ', 'condition': 'in metPC'}]"
138,P12PR8,"Next we examined the relationship between SiM-miRNAs and AR transcriptional activity in PC tissue. We determined that for 11 of the 12 SiM-miRNAs, the miRNA levels were positively correlated with the presence of a gene signature generated by silencing AR (that is, inversely correlated with AR transcriptional activity). These data further supported the role of SiM-miRNAs in the regulation of the AR axis in PC. The single outlier was miR-135a-5p, a SiM-miRNA that potently suppresses AR expression and activity, suggesting a more complex relationship to AR. Moreover, miR-135a-5p expression is generally not suppressed in primary PC (only one out of the four primary PC data sets indicated miR-135a-5p downregulation). This further suggested that silencing of miR135a-5p in metPC may be related to mechanism(s) distinct from those of the other SiM-miRNAs. Indeed, we documented that androgen potently induced the expression of miR-135a-5p, consistent with a previous report by Kroiss et al. who identified an androgen-response element in the miR-135a promoter region. Although we also found AR recruitment to the same androgen-response element under androgen stimulation of LNCaP cells with 1 nM R1881 (data not shown), we additionally identified stronger co-recruitment of AR, its pioneer factors FOXA1 and GATA2, the coactivator SRC-2, CBP, p300 and RNA Pol II to a region immediately downstream of the miR-135a-5p gene in LNCaP cells cultured without the addition of synthetic androgen. The robust presence of H3K4me1, H3K4me2 and H3K27ac, but not H3K4me3, at the latter site further suggests that it functions as an enhancer, even under normal growth conditions (medium supplemented with 10% fetal bovine serum). Combined with the inhibitory effect of miR-135a 5p on expression of AR, SRC-1, SRC-2 and SRC-3, this suggests a negative feedback loop that regulates AR axis transcriptional output and can de-repress it upon androgen deprivation. These findings also explain why miR-135a-5p was the sole outlier that lacked an inverse correlation of its levels with AR transcriptional activity in PC tissues (because the negative feedback nature of this dual interaction stabilizes this network and blunts any correlation under steady-state conditions) and why miR-135a-5p expression was not significantly downregulated in three of the four primary PC data sets that we analyzed (because they had not yet been exposed to androgen deprivation).","[{'e1': 'the miRNA levels ', 'e2': 'the presence of a gene signature generated ', 'relation': 'were positively correlated with ', 'condition': 'by silencing AR '}, {'e1': 'the role of SiM-miRNAs ', 'e2': 'the AR axis ', 'relation': 'in the regulation of ', 'condition': 'in PC'}, {'e1': 'silencing of miR135a-5p ', 'e2': 'mechanism(s) distinct from those of the other SiM-miRNAs.', 'relation': 'may be related to ', 'condition': 'in metPC'}, {'e1': 'androgen', 'e2': 'the expression of miR-135a-5p', 'relation': ' potently induced ', 'condition': ' in the miR-135a promoter region'}, {'e1': 'stronger co-recruitment of AR', 'e2': 'the miR-135a-5p gene ', 'relation': 'to a region immediately downstream of ', 'condition': 'in LNCaP cells cultured without the addition of synthetic androgen'}, {'e1': 'stronger co-recruitment of its pioneer factors FOXA1 and GATA2', 'e2': 'the miR-135a-5p gene ', 'relation': 'to a region immediately downstream of ', 'condition': 'in LNCaP cells cultured without the addition of synthetic androgen'}, {'e1': 'stronger co-recruitment of the coactivator SRC-2, CBP, p300 and RNA Pol II ', 'e2': 'the miR-135a-5p gene ', 'relation': 'to a region immediately downstream of ', 'condition': 'in LNCaP cells cultured without the addition of synthetic androgen'}, {'e1': 'a negative feedback loop ', 'e2': 'AR axis transcriptional output ', 'relation': 'that regulates ', 'condition': 'upon androgen deprivation.'}]"
139,P12PR9,"Our findings add to previously reported negative feedback loops through which AR can auto-regulate its expression: (a) AR directly binds its own gene to repress its own expression through recruitment of lysine specific demethylase 1 (LSD1/KDM1A) and H3K4me2 and H3K4me1 demethylation; and (b) androgen starvation upregulates GATA2 expression, which then binds to the AR gene promoter to induce AR expression. Of note, Lin et al. have reported a different epigenetic loop that involves regulation of AR by a miRNA: miR-31 and AR can mutually repress each other. Thus, in the context of androgen deprivation, both of them will be increased, resulting in a positive feedback loop, in contrast to the negative feedback loop of miR-135a-5p with AR. It is obviously possible that additional miRNAs can also regulate AR signaling: Östling et al. identified 71 miRNAs that influenced AR levels in human PC cells (52 decreasing and 19 increasing AR protein), although with very little overlap with the findings of our study.","[{'e1': 'additional miRNAs ', 'e2': 'AR signaling ', 'relation': 'can also regulate ', 'condition': 'in human PC cells'}]"
140,P130P10,"Similar to non- synonymous point mutations, fusion events can generate altered protein products when the fusion occurs within a coding region. In this case, the breakpoint- spanning chimeric amino acid sequence (CASQ) of two fused genes can distinguish each gene partner from its respective wild- type counterpart. Given their specificity to the tumor, these unique CASQs have the potential to elicit tumor- specific T cell responses. For instance, a multi- peptide vaccine against the CASQ of the BCR- ABL fusion protein gave rise to measureable peptide- specific immune responses and improved disease control in chronic myelogenous leukaemia patients. Despite the prevalence of genomic rearrangements across prostate cancer cases, strategies to exploit the reservoir of fusion- derived CASQs as tumor neoepitopes have not been systematically explored. Here, a stringent computational approach was used to identify prospective immunogenic fusion epitopes from transcriptomics data in a cohort of prostate adenocarcinoma patients from The Cancer Genome Atlas. While a large proportion (74 out of 85) of the cases that were examined contained gene fusions, nearly half of the patients in this analysis were found to harbor CASQs, and among these, 87% of the CASQs gave rise to predicted MHC class I epitopes. These results were even more pronounced when patients were stratified into low- and intermediate/high- risk cohorts where low- risk patients contained fewer fusions and CASQs when compared to the intermediate/high- risk patients. Interestingly, there was a significant correlation between the presence of gene fusions and CASQs with distinct immune gene expression patterns in a subset of patient tumors. Thus, immunotherapy approaches in prostate cancer should consider gene fusions and their interactions with the host immune system.","[{'e1': 'a multi- peptide vaccine against the CASQ of the BCR- ABL fusion protein ', 'e2': 'disease control ', 'relation': 'improved ', 'condition': 'in chronic myelogenous leukaemia patients'}, {'e1': ' the presence of gene fusions and CASQs ', 'e2': 'distinct immune gene expression patterns ', 'relation': 'is significantly correlated with', 'condition': 'in a subset of patient tumors'}]"
141,P130P18,"Finally, there was a significant negative relationship between tumor fusions and the presence of cytolytic immune signatures, and the number of fusions strongly stratified patients across low and intermediate/high risk groups. In general, cytolytic immune responses such as the expression of NK cell and CD8+ T cell markers negatively correlated with tumor fusions, and, to a lesser extent, predicted CASQs. Consistent with this reduction in cytolytic indicators, there was a positive association between Th2 genes. In addition to this, there was a trend towards positive associations between T regs and the presence of fusions and CASQs. Though this exploratory analysis examined on a small subset of patients, our results suggest the possibility of functional interactions between genome rearrangements and host immune responses that may impact anti- tumor immunity. It could be speculated that the negative relationship observed between tumor fusions and cytolytic immune responses may have resulted from immune selection against these potential neoantigens during tumor evolution. A similar circumstance could also exist for these immune signatures when considering the lower frequency of both fusions and CASQ in the low- versus intermediate/high- risk patients. Indeed, such a scenario may be possible as prostate cancer risk segregates with a unique immune signature based on a specific mutation profile. However, further validation in independent cohorts is needed to confirm these findings. Nonetheless, this information could expand the potential scope of mutations, including CASQs and other gene fusions, as an alternative avenue for immune- based approaches targeting prostate cancer.","[{'e1': 'the negative relationship observed between tumor fusions and cytolytic immune responses', 'e2': 'immune selection against these potential neoantigens ', 'relation': ' may have resulted from ', 'condition': 'during tumor evolution'}]"
142,P130P4,"Mutanome analysis of gene fusion- derived CASQs can give rise to patient- specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune- cell infiltration within a sub- group of prostate cancer patients.","[{'e1': 'gene fusion- derived CASQs', 'e2': 'patterns of immune- cell infiltration ', 'relation': 'predicted ', 'condition': 'within a sub- group of prostate cancer patients.'}]"
143,P130P6,"Checkpoint blockade and adoptive transfer of tumor- specific or engineered T cells are two promising approaches under investigation. Although these strategies have shown remarkable clinical responses in other cancer settings, it is believed that tumor antigen load may, in part, explain some of the differences between responders and non- responders. For example, in highly mutated solid tumors such as melanoma and non- small cell lung carcinoma (NSCLC), the success of checkpoint blockade and adoptive cell transfer (ACT) of TILs has been largely attributed to the abundance of tumor neoantigens. On the other hand, these strategies have shown less success in settings with classically low tumor mutation load, although one recent interim report found durable clinical responses to anti- PD- 1 in enzalutamide- resistant prostate cancer patients. Whether such responses in prostate cancer are associated with a higher frequency of mutations or the presence of a specific type of mutation remains to be determined.","[{'e1': 'the success of checkpoint blockade and adoptive cell transfer (ACT) of TILs ', 'e2': 'the abundance of tumor neoantigens', 'relation': 'has been largely attributed to ', 'condition': 'in highly mutated solid tumors such as melanoma and non- small cell lung carcinoma (NSCLC) '}]"
144,P131P1,"Differentiation of indolent and aggressive prostate carcinoma (PCa) at the time of diagnosis is currently one of the major challenges. This study aimed at identification of prognostic biomarkers to aid in predicting biochemical recurrence (BCR) of the disease. Microarray-based gene expression profiling in tissues of 8 BCR and 8 No-BCR cases revealed expression differences of 455 genes, most of which were down-regulated in BCR cases. Eleven genes were selected for validation by real-time PCR in the first PCa cohort (N = 55), while seven of them were further validated in the second, independent, PCa cohort (N = 53). Down-regulation of MT1E (p < 0.001) and GPR52 (p = 0.002) expression and up-regulated levels of EZH2 (p = 0.025) were specific biomarkers of BCR in at least one of the two PCa cohorts, but only MT1E expression retained the independent prognostic value in a multivariate analysis (p < 0.001). DNA methylation analysis (114 PCa and 24 non-cancerous tissues) showed frequent MT1E methylation in PCa (p < 0.001) and was associated (p < 0.010) with the down-regulated expression in one PCa cohort. The results of our study suggest MT1E down-regulation as a potential feature of aggressive PCa.","[{'e1': 'Down-regulation of MT1E (p < 0.001) expression', 'e2': 'BCR ', 'relation': 'were specific biomarkers of ', 'condition': 'in at least one of the two PCa cohorts'}, {'e1': 'Down-regulation of GPR52 (p = 0.002) expression ', 'e2': 'BCR ', 'relation': 'were specific biomarkers of ', 'condition': 'in at least one of the two PCa cohorts'}, {'e1': ' up-regulated levels of EZH2 (p = 0.025) ', 'e2': 'BCR ', 'relation': 'were specific biomarkers of ', 'condition': 'in at least one of the two PCa cohorts'}, {'e1': 'DNA methylation analysis (114 PCa and 24 non-cancerous tissues) ', 'e2': 'the down-regulated expression ', 'relation': 'was associated (p < 0.010) with ', 'condition': 'in one PCa cohort'}]"
145,P131P5,"In conclusion, our study indicates that reduced expression of MT1E is an independent predictor of poor prognosis in PCa. Measurement of MT1E level, along with other indicators of the disease progression, may serve for better prognostic stratification of PCa at the time of diagnosis or surgery.","[{'e1': 'reduced expression of MT1E ', 'e2': 'poor prognosis ', 'relation': 'is an independent predictor of ', 'condition': 'in PCa'}, {'e1': ' Measurement of MT1E level, along with other indicators of the disease progression ', 'e2': 'better prognostic stratification of PCa ', 'relation': 'may serve for ', 'condition': 'at the time of diagnosis or surgery.'}]"
146,P132P1,"Novel biomarkers for prostate cancer diagnosis and prognosis are necessary to improve the accuracy of current ones employed in clinic. We performed a retrospective study between the association of several polymorphisms in the main genes involved in the synthesis and metabolism of sex hormones and prostate cancer risk and aggressiveness. A total of 311 Caucasian men were genotyped for 9 SNPs in AR, CYP17A1, LHCGR, ESR1 and ESR2 genes. Diagnostic PSA serum levels, Gleason score, tumor stage, D’Amico risk and data of clinical progression were obtained for patients at the moment of the diagnosis and after 54 months of follow-up. Chi-squared test were used for comparisons between clinical variables groups, logistic regression for clinical variables associations between SNPs; and Kaplan–Meier for the association between SNPs and time to biochemical progression. We found 5 variants in CYP17A1, LHCGR and ESR2 that were statistically significant according to clinical variables on a case-case analysis. Moreover, the presence of A and G alleles in specific SNPs increased the risk of higher PSA levels. Several SNPs were associated with increased D’Amico risk and shorter biochemical recurrence free survival in patients with radical prostatectomy. In multigene analysis, several variants were described to be associated with more aggressiveness in patients. However, none of the selected SNPs showed significant values between patients and controls. In conclusion, this study identified inherited variants in genes CYP17A1, LHCGR and ESR2 related to more aggressiveness and poor disease progression. According to this study, new promising prostate cancer biomarkers for clinical management could be included in these SNPs.","[{'e1': ' Several SNPs ', 'e2': 'increased D’Amico risk ', 'relation': 'were associated with ', 'condition': 'in patients with radical prostatectomy'}, {'e1': ' Several SNPs ', 'e2': 'shorter biochemical recurrence free survival ', 'relation': 'were associated with ', 'condition': 'in patients with radical prostatectomy'}, {'e1': ' several variants ', 'e2': 'more aggressiveness in patients', 'relation': 'were described to be associated with ', 'condition': 'In multigene analysis'}]"
147,P133P1,"Identifying tumors with high metastatic potential is key to improving the clinical management of prostate cancer. Recently, we characterized a chromosome 16p13.3 gain frequently observed in prostate cancer metastases and now demonstrate the prognostic value of this genomic alteration in surgically treated prostate cancer. Dual-color FISH was used to detect 16p13.3 gain on a human tissue microarray representing 304 primary radical prostatectomy (RP) cases with clinical follow-up data. The results were validated in an external dataset. The 16p13.3 gain was detected in 42% (113/267) of the specimens scorable by FISH and was significantly associated with clinicopathologic features of aggressive prostate cancer, including high preoperative PSA levels, high Gleason score, advanced pathologic tumor stage, and positive surgical margins. The 16p13.3 gain predicted biochemical recurrence in the overall cohort, and in subsets of patients with PSA 10 or GS 7. Moreover, combining the 16p13.3 gain status with standard prognostic markers improved biochemical recurrence risk stratification and identified a subgroup of patients with high probability of recurrence. The 16p13.3 gain status was also associated with an increased risk of developing distant metastases, further substantiating its role in prostate cancer progression. This study demonstrates the prognostic significance of the 16p13.3 genomic gain in primary prostate tumors, suggesting potential utility in the clinical management of the disease by identifying patients at high risk of recurrence who may benefit from adjuvant therapies.","[{'e1': 'The 16p13.3 gain ', 'e2': 'biochemical recurrence ', 'relation': 'predicted ', 'condition': 'in the overall cohort'}, {'e1': 'The 16p13.3 gain ', 'e2': 'biochemical recurrence ', 'relation': 'predicted ', 'condition': ' in subsets of patients with PSA 10 or GS 7'}]"
148,P133P3,"Genomic profiling studies have highlighted disease heterogeneity, suggesting alternative molecular pathways driving prostate cancer development. Lapointe and colleagues have reported high frequency of DNA copy number alterations in prostate cancer lymph node metastases including a gain of 16p13, 8q24 and deletion of 10q23 and 16q23. These copy number alterations represent potential prognostic biomarkers that can be assessed in routine formalin-fixed paraffin-embedded tissue sections using specific DNA probes by FISH. We recently mapped the previously uncharacterized focal 16p13.3 genomic gain in primary prostate tumors and identified PDPK1 encoding 3-phosphoinositide-dependent protein kinase-1 as a likely driver of the gain with functional impact on prostate cancer cell migration. The current study, for the first time, demonstrates that 16p13.3 genomic gain is a predictor of poor clinical outcome in patients treated by radical prostatectomy that can aid to better risk stratify these patients when combined with standard clinicopathologic prognostic markers.","[{'e1': '16p13.3 genomic gain ', 'e2': 'poor clinical outcome ', 'relation': 'is a predictor of ', 'condition': 'in patients treated by radical prostatectomy '}]"
149,P134P5,"Prostate cancer is the most commonly diagnosed genital malignant disease in men, with an estimated 220 800 newly diagnosed cases and 27 540 deaths in 2015 in the USA. In addition, the morbidity rate of prostate cancer has recently been increasing in China. Currently, with the use of prostate-specific antigen and prostate biopsy for prostate cancer screening, more and more patients can be diagnosed in the early stage and treated by radical prostatectomy. However, about 25–50% of prostate cancer patients will have tumor recurrence after surgery, and many will die of the cancer. Although current clinicopathological features such as Gleason score, disease stage, and PSA level provide important information, they do not accurately predict an individual patient’s prognosis, and new biomarkers are needed for prognostication.","[{'e1': 'about 25–50% of prostate cancer patients ', 'e2': 'tumor recurrence ', 'relation': 'will have ', 'condition': 'after surgery'}]"
150,P134P6,"Prostate cancer is a heterogeneous disease; genetic and epigenetic mechanisms are involved in the initiation and progression of the disease and may be used as potential biomarkers. DNA methylation is the most common epigenetic event in human cancer. Growing evidence indicates that aberrant DNA methylation has potential to improve the accuracy of human cancer prognosis. PCDH8, belonging to the cadherin super-family, plays crucial functions in cell adhesion, proliferation, differentiation, and migration. Previous reports indicated that PCDH8 functions as a tumor suppressor and is often silenced by aberrant promoter methylation in human cancers, including prostate cancer. In our previous study, we confirmed that PCDH8 was often methylated in prostate cancer tissues, and was correlated with malignant behaviors and poor outcome of the disease. However, little is known about the clinical significance of PCDH8 methylation in serum of prostate cancer, especially in low Gleason score cases.","[{'e1': 'PCDH8 ', 'e2': 'a tumor suppressor ', 'relation': 'functions as ', 'condition': 'in human cancers'}, {'e1': 'PCDH8 ', 'e2': 'aberrant promoter methylation ', 'relation': 'is often silenced by ', 'condition': 'in human cancers'}]"
151,P134P8,"In conclusion, we characterized PCDH8 methylation in serum of prostate cancer patients with low Gleason score and analyzed its relationship to classical clinicopathological parameters and patient outcomes. We found that PCDH8 methylation in serum is an independent risk factor for the biochemical recurrence of low Gleason score prostate cancer patients after surgery, and can be used as a potential prognostic biomarker. In the future, the methylation status of PCDH8 in serum should be checked before surgery, and for the patients with PCDH8, methylation hormonal therapy should be performed after surgery, so as to prevent tumor recurrence and achieve better prognosis.","[{'e1': 'PCDH8 methylation in serum ', 'e2': ' the biochemical recurrence of low Gleason score prostate cancer patients', 'relation': 'is an independent risk factor for', 'condition': ' after surgery'}]"
152,P135P7,"Gene expression biomarkers have shown promise for prostate cancer risk stratification, particularly in men undergoing radical prostatectomy. Few studies have assessed gene expression biomarkers in formalin-fixed paraffin-embedded diagnostic biopsies in men treated with primary radiotherapy, likely due to small tissue samples that may have degraded.","[{'e1': 'Gene expression biomarkers ', 'e2': 'prostate cancer risk stratification', 'relation': 'have shown promise for ', 'condition': 'particularly in men undergoing radical prostatectomy.'}]"
153,P138P6,"In PCa, loss of PTEN has been consistently associated with more aggressive disease features and a worse prognosis. Estimates of PTEN loss range from less than 20 percent for clinically localized prostate tumors to more than 40 percent for metastatic castrate-resistant PCa. PTEN loss also frequently co-occurs with the TMPRSS2:ERG gene fusion, which exists in about half of all localized prostate tumors in men of European ancestry, suggesting that both somatic events might cooperate in prostate tumorigenesis. Loss of PTEN is now recognized as one of the major driving events in PCa.","[{'e1': ' loss of PTEN ', 'e2': 'more aggressive disease features ', 'relation': 'has been consistently associated with ', 'condition': 'In PCa'}, {'e1': ' loss of PTEN ', 'e2': 'a worse prognosis', 'relation': 'has been consistently associated with ', 'condition': 'In PCa'}]"
154,P138P7,"Tumors with PTEN loss have significantly altered gene expression profiles. Saal et al. previously generated a tumor transcriptomic signature of PTEN loss in breast tumors. The signature included 246 genes and the most significant differentially expressed gene was PTEN itself. The PTEN loss-like mRNA expression signature was also strongly associated with PTEN status based on copy number levels in PCa. Further, in independent datasets of breast, prostate, and bladder carcinoma, the signature significantly correlated with worse patient outcomes.","[{'e1': 'The PTEN loss-like mRNA expression signature ', 'e2': ' PTEN status ', 'relation': 'was also strongly associated with', 'condition': 'based on copy number levels in PCa'}, {'e1': ' the signature', 'e2': 'worse patient outcomes.', 'relation': ' significantly correlated with ', 'condition': 'in independent datasets of breast carcinoma'}, {'e1': ' the signature', 'e2': 'worse patient outcomes.', 'relation': ' significantly correlated with ', 'condition': 'in independent datasets of prostate carcinoma'}, {'e1': ' the signature', 'e2': 'worse patient outcomes.', 'relation': ' significantly correlated with ', 'condition': 'in independent datasets of bladder carcinoma'}]"
155,P139P1,CPNE1 plays a vital role in regulating cell differentiation. The clinical and biological values of CPNE1 in prostate cancer are still unclear. The aim of this study was to investigate the clinicopathological value of CPNE1 and the association of CPNE1 with TRAF2 expression in patients with prostate cancer.,"[{'e1': ' CPNE1 ', 'e2': 'TRAF2 expression ', 'relation': 'is associated with', 'condition': 'in patients with prostate cancer.'}]"
156,P139P3,"Our results showed that expression level of CPNE1 is higher in prostate cancer than in normal prostate tissues. In the GSE35988 dataset, CPNE1 expression was found to be upregulated in castration-resistant prostate cancer compared with non-castration-resistant prostate cancer. Furthermore, we found that CPNE1 high expression was significantly related to tumor stage, Gleason score, and poorer biochemical recurrence-free survival in prostate cancer patients. Co-expression analysis of TCGA data showed that CPNE1 is significantly associated with TRAF2 expression. CPNE1 overexpression can upregulate TRAF2 expression in prostate cancer DU-145 cells as determined by Western blotting and immunofluorescence assays.","[{'e1': ' CPNE1 high expression ', 'e2': 'tumor stage', 'relation': 'was significantly related to ', 'condition': 'in prostate cancer patients'}, {'e1': ' CPNE1 high expression ', 'e2': 'Gleason score ', 'relation': 'was significantly related to ', 'condition': 'in prostate cancer patients'}, {'e1': ' CPNE1 high expression ', 'e2': 'poorer biochemical recurrence-free survival ', 'relation': 'was significantly related to ', 'condition': 'in prostate cancer patients'}, {'e1': ' CPNE1 overexpression ', 'e2': 'TRAF2 expression', 'relation': 'can upregulate ', 'condition': ' in prostate cancer DU-145 cells'}]"
157,P139P4,"Overall, our findings suggest that CPNE1 is a valuable prognostic marker for evaluating recurrence-free survival and is positively related to TRAF2 expression in prostate cancer.","[{'e1': ' CPNE1 ', 'e2': 'TRAF2 expression ', 'relation': 'is positively related to ', 'condition': 'in prostate cancer.'}]"
158,P139P5,"Prostate cancer is one of the most common cancer types in aging men. There were approximate 220 800 new cases and 27 540 deaths in the United States in 2015. The incidence rate of prostate cancer has also been increasing in Asian populations. Different treatments, including surgical resection, radiological therapy, and androgen deprivation therapy, can be used to treat patients with localized prostate cancer. However, prostate cancer eventually progresses to an androgen-refractory state in most patients, which is also known as castration-resistant prostate cancer. Castration-resistant prostate cancer is relatively resistant to androgen deprivation therapy treatment and can influence approximate 20% of prostate cancer patients in 5 years. However, the underlying mechanisms governing the development and progression of prostate cancer remain unclear.","[{'e1': 'prostate cancer ', 'e2': 'an androgen-refractory state ', 'relation': 'eventually progresses to ', 'condition': 'in most patients'}]"
159,P139P6,"CPNE1 is a member of the calcium-dependent lipid-binding protein family. Currently, 9 family members have been reported in studies. It is reported that Copine1, encoded by CPNE1, is a soluble membrane-binding protein, which includes 2 tandem C2 domains at the N-terminus and an A domain at the C-terminus. Copine1 can bind with different intracellular proteins via its A domain at the C-terminus. In addition, Copine1 can also exhibit calcium-dependent phospholipid binding activity via its C2 domain. Park et al. reported that Copine1 plays a vital role in regulating neuronal differentiation of HiB5 cells, which may be related to activating Akt signaling. Akt has been found to be involved in various biological processes, including cell migration, invasion, and survival. It was reported that CPNE1 can promote neuronal differentiation via phosphorylating Akt on the residue 473. Currently, the effects of CPNE1 on development and progression of prostate cancer are not well understood.","[{'e1': 'Copine1 ', 'e2': 'different intracellular proteins ', 'relation': 'can bind with ', 'condition': 'via its A domain at the C-terminus'}, {'e1': 'Copine1', 'e2': 'calcium-dependent phospholipid binding activity ', 'relation': ' can exhibit ', 'condition': 'via its C2 domain'}, {'e1': 'CPNE1 ', 'e2': 'neuronal differentiation ', 'relation': 'can promote ', 'condition': 'via phosphorylating Akt on the residue 473'}]"
160,P139P7,"Tumor necrosis factor receptor-associated factor 2, as an adaptor protein, belongs to the TRAF family. Seven members have been identified in the TRAF family. TRAF2 expression is upregulated in multiple cancer types and is a valuable prognostic biomarker in patients. It was reported that TRAF2 expression is increased in gastric cancer and can be a novel diagnostic and prognostic biomarker in gastric cancer patients. In addition, the expression level of TRAF2 is higher in malignant pleural effusion cells than in normal breast samples in breast cancer patients. Further study showed that TRAF2 is an important prognostic biomarker in patients. Our study also indicated that TRAF2 expression in prostate cancer is upregulated and can be a valuable prognostic marker in prostate cancer patients. However, the relationship between CPNE1 and TRAF2 expression is not clear.","[{'e1': 'TRAF2 expression ', 'e2': 'valuable prognostic biomarker ', 'relation': 'is a ', 'condition': 'in patients'}, {'e1': ' TRAF2 expression ', 'e2': 'novel diagnostic and prognostic biomarker ', 'relation': 'can be a ', 'condition': 'in gastric cancer patients'}, {'e1': 'the expression level of TRAF2 ', 'e2': 'in malignant pleural effusion cells than in normal breast samples ', 'relation': 'is higher ', 'condition': 'in breast cancer patients'}, {'e1': 'TRAF2 expression in prostate cancer ', 'e2': 'valuable prognostic marker ', 'relation': 'can be a ', 'condition': 'in prostate cancer patients.'}]"
161,P139P8,"In this report, our findings showed that CPNE1 expression is significantly increased in prostate cancer. CPNE1 expression is related to tumor stage and Gleason score. A novel finding is that CPNE1 expression is significantly related to TRAF2 expression. CPNE1 overexpression can upregulate TRAF2 expression in prostate cancer DU-145 cells. Overall, CPNE1 is a novel prognostic factor to predict biochemical recurrence-free survival and is positively related to TRAF2 expression in prostate cancer.","[{'e1': ' CPNE1 overexpression ', 'e2': 'TRAF2 expression ', 'relation': 'can upregulate ', 'condition': 'in prostate cancer DU-145 cells'}, {'e1': 'CPNE1 ', 'e2': 'TRAF2 expression ', 'relation': 'is positively related to ', 'condition': 'in prostate cancer.'}]"
162,P139P9,"We found that CPNE1 expression is significantly increased in prostate cancer. Based on the GEO dataset, increased CPNE1 expression was further identified in castration-resistant prostate cancer, and CPNE1 expression was found to be significantly related to tumor stage and Gleason score. In addition, our results showed that CPNE1 expression is significantly associated with TRAF2 expression. Overall, CPNE1 is a valuable prognostic marker for predicting recurrence-free survival and is positively associated with TRAF2 expression in prostate cancer.","[{'e1': 'CPNE1 ', 'e2': 'TRAF2 expression ', 'relation': 'is positively associated with ', 'condition': 'in prostate cancer.'}]"
163,P13P13,"We wanted to determine the direct implications of the candidate genes on AI growth. For this, four genes, which include three top candidate genes (GLYATL1, STRA13, FAM83H) and a gene that had CISs (KDM2A) were selected for validation. An additional criteria was that these genes were not been previously implicated with PC progression. First an in vitro clonogenic assay was performed to determine the effect on proliferation of LNCaP and next investigated the implications gene knockdown on AIPC progression. Significant reduction in the clonogenic ability of the LNCaP cells by knocking down KDM2A, FAM83H and GLYATL1 suggest that these three genes might be associated in promoting proliferation of LNCaP cells. We were the first to show that KDM2A, FAM83H and GLYATL1 knockdown reduces proliferation rate of PC cells. Further, in the proliferation recovery assay it was KDM2A gene knockdown that had a significant effect on recovery, indicating that KDM2A might play a role in recovering of PC cells from the proliferative arrest induced by castration. Interestingly, our proviral integration site analysis revealed CISs in the KDM2A gene and each of these integration site was recovered at a high frequency. These results suggest that the clones with a dysregulation of KDM2A gene by the proviral integration might had a growth advantage and were enriched in the castrated mice. Previously KDM2A was reported to be upregulated in gastric and lung cancers, and the knockdown of KDM2A was shown to suppress tumorigenicity and invasion of gastric cancer [78] and non-small cell lung cancer cells. Though FAM83H and GLYATL1 had not shown any effect in the proliferative recovery assay, implication of these gene in AIPC progression needs further investigations. Migration and invasion studies could shed some more light regarding the association of the candidate genes in AIPC progression.","[{'e1': 'the clones with a dysregulation of KDM2A gene by the proviral integration ', 'e2': 'growth advantage and were enriched ', 'relation': 'might had a ', 'condition': 'in the castrated mice'}]"
164,P13P14,"In addition to identifying genes related to PC progression, our study identified that these candidate genes were prognostic for recurrence risk in PC patients after treatment. The dataset we used for our prognostication studies measured recurrence risk based on PSA levels. Two of our candidate genes, ARFGAP3 and CLDN7, were previously shown to regulate PSA in PC cells. This could be the reason why the prognostic value of combinations comprising these two genes showed a highly predictive ability to predict the clinical outcome of PC patients. As expected using multiple biomarkers improved the predictive accuracy of PC over the use a single biomarker.","[{'e1': ' candidate genes ', 'e2': 'recurrence risk ', 'relation': 'were prognostic for ', 'condition': 'in PC patients '}, {'e1': ' candidate genes ', 'e2': 'recurrence risk in PC patients ', 'relation': 'were prognostic for ', 'condition': 'after treatment'}, {'e1': 'The dataset we used for our prognostication studies ', 'e2': ' recurrence risk', 'relation': ' measured', 'condition': ' based on PSA levels'}, {'e1': ' ARFGAP3 and CLDN7 ', 'e2': 'PSA ', 'relation': 'were previously shown to regulate ', 'condition': 'in PC cells'}]"
165,P13P15,"Taken together our studies identified novel genes which are differentially expressed and recurrently altered in PC samples. However these genes need further study to confirm their involved in AIPC. Importantly, the candidate genes identified in our screen predicted the recurrence risk in PC patients after prostatectomy, suggesting genetic testing of these candidate genes might predict recurrence risk in the patients. Moreover, our validation demonstrated that suppression of KDM2A could potential block the emergence of AIPC cells following ADT, which might be used as a potential therapeutic target in AIPC. Further, future studies on these genes might be explored to determine if they can be used to predict the therapeutic options to have the best clinical outcome.","[{'e1': 'the candidate genes identified in our screen', 'e2': 'the recurrence risk ', 'relation': ' predicted ', 'condition': 'in PC patients after prostatectomy'}, {'e1': ' genetic testing of these candidate genes', 'e2': 'recurrence risk ', 'relation': ' might predict ', 'condition': 'in the patients'}, {'e1': ' suppression of KDM2A ', 'e2': 'the emergence of AIPC cells ', 'relation': 'could potential block ', 'condition': 'following ADT'}]"
166,P13P3,"Prostate cancer (PC) is the most commonly diagnosed cancer in men and the second leading cause of cancer related deaths in United States. The five year survival rate of PC is almost 100% if diagnosed early. However the rate drops to ~30% if diagnosed late or once it has metastasized to distant organs. Localized primary PC is treated by prostatectomy or radiotherapy, but often patients develop metastatic disease. PC progression is dependent on androgen levels, therefore halting the androgen supply to the cancerous cells using anti androgen drugs (androgen deprivation therapy, ADT) has been the frontline option for treatment of metastatic PC. Though patients initially respond positively to ADT, in almost all patients the tumor recurs. The recurrent tumor, clinically referred as androgen independent prostate cancer (AIPC), is aggressive and no longer responds to ADT. AIPC is usually lethal, with an average life expectancy of less than 5 years","[{'e1': 'Prostate cancer (PC) ', 'e2': 'diagnosed cancer ', 'relation': 'is the most commonly ', 'condition': 'in men'}, {'e1': 'Prostate cancer (PC) ', 'e2': 'cause of cancer related deaths ', 'relation': 'the second leading ', 'condition': 'in United States'}, {'e1': 'the rate ', 'e2': '~30% ', 'relation': 'drops to ', 'condition': 'if diagnosed late or once it has metastasized to distant organs'}, {'e1': 'patients ', 'e2': ' ADT', 'relation': 'initially respond positively to', 'condition': 'in almost all patients the tumor recurs'}]"
167,P13P4,"The molecular basis for this progression from androgen sensitive to AIPC after treatment is one of the most extensively studied areas in the field of PC. Several genes have been linked to the progression of PC into AIPC, but the molecular mechanisms responsible for AIPC progression are still poorly defined. High-throughput techniques have been used to discover genes that are altered/mutated and differentially expressed between androgen sensitive and androgen insensitive PC. However, differentiating gene mutations that actually drive AIPC from bystander mutations is a major challenge. Identifying the driver genetic mutations responsible for AIPC is critical for improving our ability to predict recurrence and for developing new therapeutics to increase the life expectancy of PC patients.","[{'e1': 'The molecular basis for this progression from androgen sensitive to AIPC after treatment ', 'e2': 'most extensively studied areas', 'relation': 'is one of the ', 'condition': ' in the field of PC'}]"
168,P13P6,"Here we report for the first time an insertional mutagenesis screen in an orthotopic xenograft mouse model to identify genes involved in AIPC. In this approach, mutagenized-LNCaP cells were directly injected into the prostate of male immunodeficient mice. After tumors formed, mice were castrated to select for androgen independent tumors in vivo, modeling what occurs in PC patients. This human xenograft PC orthotopic model has the advantage that genes promoting AIPC in the prostate microenvironment can potentially be identified. We identified several interesting genes using this screen and established their ability to predict recurrence after ADT.","[{'e1': 'an insertional mutagenesis screen in an orthotopic xenograft mouse model ', 'e2': 'genes involved ', 'relation': 'to identify ', 'condition': 'in AIPC'}, {'e1': 'mice were castrated ', 'e2': 'androgen independent tumors ', 'relation': 'to select for ', 'condition': 'after tumors found'}, {'e1': 'mice were castrated ', 'e2': 'androgen independent tumors ', 'relation': 'to select for ', 'condition': 'in vivo, modeling what occurs in PC patients'}, {'e1': 'several interesting genes ', 'e2': ' recurrence ', 'relation': ' to predict', 'condition': 'after ADT.'}]"
169,P13P7,"Insertional mutagenesis screens are valuable tools for discovering novel genes associated with cancer. Here for the first time, we have performed a LV-mediated insertional mutagenesis screen in an orthotopic mouse model to discover genes associated with PC. Injection of LV-mutagenized LNCaP cells into the mouse prostate efficiently developed tumors in mouse prostates approximately 3 weeks after injections and these tumors regressed after castration. Similar to PC progression post ADT in cancer patients we observed that tumors reemerged in the castrated mice. Re-emergence of AIPC from androgen responsive PC has been implicated due to various mechanism, including acquiring genetic alteration that support progression of AIPC. We reasoned that tumors that develop in castrated mice have a selective advantage to proliferate in an androgen deficient environment. We hypothesize that these tumors gain this advantage due to provirus integrations dysregulating nearby genes, thereby triggering AIPC.","[{'e1': ' genes ', 'e2': 'with PC', 'relation': 'associated ', 'condition': ' in an orthotopic mouse model'}, {'e1': 'tumors that develop in castrated mice', 'e2': 'selective advantage to proliferate ', 'relation': ' have a ', 'condition': 'in an androgen deficient environment'}]"
170,P13P8,"Analyzing the proviral integration sites, we identified 11 promising candidate genes. Three of the candidate genes were identified in/near CISs and another eight candidate genes were identified by performing meta-analysis of all genes in/near the 79 tumor unique integrations sites from androgen independent primary tumor samples. Meta-analysis enabled us to prioritize the candidate genes that are differentially expressed in human PC samples. In addition to differentially expression, cancer-associated genes are mostly known to be genetically altered in cancer patients. It has been shown that PC progression is most often the result of chromosomal rearrangements and gene mutations. The loss/mutations of TP53 and PTEN are common genetic alterations found in AIPC. In addition to PTEN and TP53, several other genetic alterations were reported to be important for AIPC emergence. Our analysis demonstrated that at least four of our candidate genes (FAM83H, OBSCN, CLDN7 and STRA13) were recurrently altered in PC patients, suggesting that dysregulation of these candidate genes might have triggered AIPC in our screen.","[{'e1': 'eight candidate genes ', 'e2': 'meta-analysis of all genes ', 'relation': 'were identified by performing ', 'condition': 'in/near the 79 tumor unique integrations sites from androgen independent primary tumor samples'}, {'e1': 'Meta-analysis', 'e2': 'the candidate genes that are differentially expressed ', 'relation': ' enabled us to prioritize ', 'condition': 'in human PC samples'}, {'e1': 'cancer-associated genes ', 'e2': 'genetically altered ', 'relation': 'are mostly known to be ', 'condition': 'in cancer patients'}, {'e1': 'dysregulation of these candidate genes ', 'e2': 'AIPC ', 'relation': 'might have triggered ', 'condition': 'in our screen'}]"
171,P140P1,"Due to insufficient prognostic tools, failure to predict aggressive prostate cancer has left patient selection for radical treatment an unsolved challenge. This has resulted in overtreatment with radical therapy. Better prognostic tools are urgently warranted. MicroRNAs have emerged as important regulators of cellular pathways, resulting in altered gene expressions. miR-205 has previously been observed downregulated in prostate cancer, acting as tumor suppressor. Herein, the expression of miR-205 in prostate tissue was examined in a large, well-described cohort of 535 Norwegian prostatectomy patients. Using in situ hybridization, miR-205 expression was semiquantatively measured in normal and tumor tissues from radical prostatectomy specimens. Associations with clinicopathological data and prostate cancer relapse were calculated. Expression of miR-205 was lower in tumor epithelium compared to normal epithelium. No association was observed between miR-205 expression in primary tumor epithelium and cancer relapse. In contrast, high expression of miR-205 in normal epithelium was independently associated with biochemical relapse. A prognostic importance of miR-205 expression was only found in the normal epithelium, raising the hypothesis of epithelial crosstalk between normal and tumor epithelium in prostate cancer. This finding supports the proposed novel hypothesis of an anti-cancerogenous function of normal epithelium in tumor tissue.","[{'e1': 'miR-205 expression', 'e2': ' normal and tumor tissues from radical prostatectomy specimens', 'relation': ' was semiquantatively measured in', 'condition': 'Using in situ hybridization'}, {'e1': 'high expression of miR-205 ', 'e2': 'biochemical relapse', 'relation': 'was independently associated with ', 'condition': 'in normal epithelium'}]"
172,P140P3,"The micro-RNAs are small noncoding RNAs regulating protein expression and numerous cellular processes. These are involved in the normal functioning of cells, while dysregulations of miRs are associated with disease. Various dysregulations of certain miRs associated with specific cancers have been identified, and they may have either tumor suppressor or oncogenic functions able to modulate nearly all stages of cancer progression including proliferation, apoptosis, cell migration, angiogenesis and stem cell maintenance. miR-205 acts either as an oncogene or as a tumor suppressor by facilitating or repressing tumor initiation and proliferation depending on type of cancer and stage. Recently, there has been a major effort to target these non-coding RNAs therapeutically, and a few miRs have entered preclinical and clinical trials. While studies have demonstrated that miR-205 in general is involved in both normal development and cancer, the prognostic role of miR-205 in prostate cancer is not unambiguously clarified in prostate cancer. miR-205 is found to be downregulated in prostate cancer tissue compared to benign tissues, and loss of miR-205 seems to be associated with an invasive phenotype and poor clinical outcome. miR-205 has a tumor suppressive function by inhibiting the transition from epithelial to mesenchymal tissue, cell migration and invasion in the prostate. In a recent study carried out in prostate cancer clinical samples, miR-205 was demonstrated to act against tumor initiation and progression by basement membrane maintenance or repressing the mitogen-activated protein kinase and androgen receptor-signaling pathway. However, high miR-205 expression has also been associated with adverse outcome in prostate cancer patients. Since miR-205 was consistently downregulated for a selected group of 14 prostate cancer patients with rapid biochemical failure in our previous screening array of 1435 miRs in tumor tissue, we set out to investigate the prognostic role of miR-205 in our large and well-described cohort of 535 Norwegian prostatectomy patients with extensive follow-up.","[{'e1': 'miR-205 ', 'e2': 'an oncogene or as a tumor suppressor ', 'relation': 'acts as ', 'condition': 'by facilitating or repressing tumor initiation and proliferation depending on type of cancer and stage'}, {'e1': 'high miR-205 expression ', 'e2': 'adverse outcome', 'relation': 'has also been associated with ', 'condition': ' in prostate cancer patients'}]"
173,P142P2,"Prostate cancer is the most commonly diagnosed form of cancer for men in both Canada and the United States. Deaths attributed to prostate cancer began declining since the mid-1990s after the discovery of the Prostate-Specific Antigen (PSA) in early 1980s. Decreased mortality is likely result of both advancements in traditional therapies and diagnostic techniques, as well as PSA used for early diagnosis, later being somewhat controversial.","[{'e1': 'Deaths attributed to prostate cancer ', 'e2': 'the mid-1990s ', 'relation': 'began declining since ', 'condition': 'after the discovery of the Prostate-Specific Antigen (PSA) in early 1980s'}]"
174,P142P9,"Various groups have used a systems biology approach (quantitation of expression and pattern of expression of multiple molecular markers that have shown to have an association with prostate cancer and aggressive behavior) to predict pathology with some success. However, these were not based on quantifying the distribution of DNA within the nuclei of the effected cells. Some have shown that AMACR IHC and AR (androgen receptor) IHC are useful in predicting which lesions are of risk to the patient. Others have shown that IHC for detecting ERG over expression improves diagnosis of prostate cancer over AMACR and basal cell markers as well as being highly correlated with TMPRSS2:ERG fusions which have been associated with poor prognosis in watchful waiting cohorts. Further, there is excellent evidence that chromatin remodeling plays a significant role in a large fraction of prostate cancers, particularly that mutations in SPOP and CHD1 (which encodes for a DNA binding protein that acts to remodel chromatin states) are very frequent in prostate cancer. This is particularly interesting in that SPOP/CHD1 mutations appear to be mutually exclusive from the family of TMPRSS2:ERG fusions. This is an example of the heterogeneous pathways of neoplastic development in the prostate. Given that SPOP/CHD1 encodes for a DNA binding protein that acts to remodel chromatin states it is not unreasonable to hypothesize that the measurements of chromatin states within nuclei should synergize well with ERG expression with respect to predicting biological behavior. Others have recognized the importance of chromatin phenotypic alterations to predict the biological behavior of prostate cancer. Ventri and Christudass present a nice summary of how genetic alterations can result in detectable changes in chromatin organization that predict prostate biological behavior alone or in combination with conventional biomarkers such as Gleason score.","[{'e1': 'TMPRSS2:ERG fusions ', 'e2': 'poor prognosis ', 'relation': 'have been associated with ', 'condition': 'in watchful waiting cohorts'}]"
175,P143P4,"Single nucleotide mutations, small indels, copy number estimates, and expression profiles were identified. Phylogenetic relationships between coincident foci were determined, and characteristics distinguishing ductal from acinar foci were identified. Results and limitations: Exome sequencing, copy number estimates, and fusion genes demonstrated coincident ductal and acinar adenocarcinoma diverged from a common progenitor, yet they harbored distinct alterations unique to each focus. AR expression and activity were similar in both histologies. Nine of 10 cases had mutually exclusive CTNNB1 hotspot mutations or phosphatase and tensin homolog alterations in the ductal component, and these were absent in the acinar foci. These alterations were associated with changes in expression in WNT- and PI3K-pathway genes. Conclusions: Coincident ductal and acinar histologies typically are clonally related and thus arise from the same cell of origin. Ductal foci are enriched for cases with either a CTNNB1 hotspot mutation or a PTEN alteration, and are associated with WNT- or PI3K-pathway activation. These alterations are mutually exclusive and may represent distinct subtypes.","[{'e1': ' These alterations ', 'e2': 'changes in expression ', 'relation': 'were associated with ', 'condition': 'in WNT- and PI3K-pathway genes'}]"
176,P144P2,"The American Cancer Society estimates 160,000 new cases of prostate cancer in 2017 and expects 26,000 patients to die from prostate cancer. Prostate cancer prognosis is often favorable, especially when the disease is organ-confined as 5-year survival rates of over 95% show. The total removal of the prostate, called radical prostatectomy, if necessary in combination with the radical removal of pelvic lymph nodes, offers curative treatment. Apart from surgery, external beam radiation or the implantation of radioactive metal seeds into the prostate, called brachytherapy, is a further treatment possibility. However, prostate cancer returns in 15% to 30% of all cases as local relapse or in terms of metastases. Especially in metastatic state, the survival rates drop to around 28%. Prostate cancer metastasizes predominantly via the lymphatic drainage ways to local lymph nodes in the small pelvis, for example to those alongside the iliacal vessels, in the fossa obturatoria, or presacral. In advanced stages or in case of relapse, prostate cancer often affects also aortal or caval lymph nodes, which are classified as distant metastases.","[{'e1': 'prostate cancer ', 'e2': 'aortal or caval lymph nodes', 'relation': 'often affects ', 'condition': 'In advanced stages or in case of relapse'}]"
177,P145P5,"Prostate cancer is the most common cancer by incidence and second most lethal cancer in American males. DNA methylation and histone tail modification are two key epigenetic processes that play vital roles in prostate cancer progression. Histone post-translational modifications including acetylation, methylation, and phosphorylation exist in a highly specific fashion and function to influence gene transcription by interconverting chromatin from its permissive and repressive states. Histone acetyl transferases and deacetylases are enzymes that add or remove acetyl groups on the lysine residues in the N terminal chains of histones. Addition of acetyl groups to histones affects the stability of nucleosomes and alters the access of DNA binding proteins to their recognition sites. The presence of acetylated histones in nucleosomes near transcriptional start sites are generally associated with gene transcription. The histone modulating enzymes can be targeted to specific regions of the genome and show degrees of substrate specificity, properties that are consistent with a role in maintaining a dynamic, acetylation-based epigenetic code.","[{'e1': 'The presence of acetylated histones ', 'e2': 'gene transcription', 'relation': 'are generally associated with ', 'condition': 'in nucleosomes near transcriptional start sites'}]"
178,P145P6,"Altered abundance of acetyl marks on lysine residues on histone 4 and histone 3 are common in several cancers and have prognostic information. Furthermore, it is possible to differentiate between benign and malignant prostatic tissue based on certain epigenetic characteristics. For example, Seligson et al. have shown stratifying primary prostatectomy tissue samples by overall acetylated H3 and H4 immunostaining predicted tumor recurrence in patients with low-grade prostate cancers. Similarly, acetylation of H3 and trimethylation of H4 have also been used in combination with preoperative serum PSA to predict the likelihood of recurrence in high-grade prostate cancers.","[{'e1': 'stratifying primary prostatectomy tissue samples by overall acetylated H3 and H4 immunostaining ', 'e2': ' tumor recurrence', 'relation': 'predicted', 'condition': ' in patients with low-grade prostate cancers'}, {'e1': 'acetylation of H3 and trimethylation of H4 ', 'e2': 'the likelihood of recurrence', 'relation': 'have also been used to predict ', 'condition': ' in high-grade prostate cancers.'}]"
179,P145P7,"P300 protein is a ubiquitously expressed histone acetyl transferase that regulates a diverse range of cellular functions including cell growth, differentiation and survival. While P300 is capable of acetylating several histone lysines in vitro, H3K18 appears to be a target unique to P300 as P300 knockdown causes global hypoacetylation at this site. The catalytic activity of P300 is regulated by an evolutionary conserved autoacetylation loop at K1499 and this loop is modified by several factors including deacetylases such as the Sirtuins. Sirtuins are a group of proteins that function in cellular metabolism, chromatin stability, and DNA repair. Among the seven known mammalian Sirtuins, SIRT2 can function as a tumor suppressor and its knockdown has been shown to induce gender-specific tumorigenesis in mice. SIRT2 is a key deacetylase of the P300 K1499 site in vitro and in vivo studies and SIRT2 knockdown causes P300 to attain a hyperacetylated state, which is associated with higher acetyltransferase activity. The deacetylase activity of SIRT2 maintains H3K18Ac in check, thereby exerting a controlling influence on the transcription process. P300 on the other hand can potentiate its own activity by autoacetylation and by inhibiting the activity of SIRT2 by acetylation. Thus, there is reciprocal regulation between P300 and SIRT2 that serves to maintain epigenetic homeostasis.","[{'e1': "" SIRT2's knockdown "", 'e2': 'gender-specific tumorigenesis ', 'relation': 'has been shown to induce ', 'condition': 'in mice'}]"
180,P147P6,"The PTEN gene is located at 10q23.31 and mapping studies have shown that PTEN genomic deletions in prostate cancer vary in size from a few hundred kb of DNA to several Mb. Interestingly, PTEN deletions often appear to have breakpoints that initiate close to low copy repeat regions. The low copy repetitive elements, also known as segmental duplications, are unstable DNA sequences that are represented two or more times in the genome with high sequence identity, but not arising by retrotransposition. On chromosome 10 there is one low copy repeat hotspot 400 kb centromeric of PTEN that may facilitate the inter- and intragenomic alterations leading to PTEN loss. Low copy repeats can promote the occurrence of somatic copy number alterations through non-allelic homologous recombination, non-homologous end-joining, and fork stalling and template switching. To date, PTEN gene deletions have been extensively analyzed through FISH assays, but a detailed mapping of chromosome 10 deletions that span PTEN and their impact on somatic copy number alterations and levels of aneuploidy in prostate cancer outcome have not been investigated in detail.","[{'e1': ' Low copy repeats ', 'e2': 'the occurrence of somatic copy number alterations ', 'relation': 'can promote ', 'condition': 'through non-allelic homologous recombination'}, {'e1': ' Low copy repeats ', 'e2': 'the occurrence of somatic copy number alterations ', 'relation': 'can promote ', 'condition': 'through non-homologous end-joining'}, {'e1': ' Low copy repeats ', 'e2': 'the occurrence of somatic copy number alterations ', 'relation': 'can promote ', 'condition': 'through fork stalling '}, {'e1': ' Low copy repeats ', 'e2': 'the occurrence of somatic copy number alterations ', 'relation': 'can promote ', 'condition': 'throught template switching'}]"
181,P148P5,"In this study, we demonstrate that the size of heterozygous deletions in human prostate cancer greatly correlates with tumor progression and aggressiveness. That we made this observation in two of the most frequently deleted loci, i.e., 6q and 16q, and that the vast majority of deletions in prostate cancer typically affect large chromosomal segments, suggests that extensive loss of chromosomal material by progressive “deletion lengthening” is a key mechanism for simultaneous dosage reduction of multiple genes. Co-depletion of arbitrarily selected candidate tumor suppressor genes located inside the large 6q12-q22 deletion region identified 4 genes, including UBE2J1, ZNF292, SMAP1, and HMGN3 as a prime example for assumedly many more genes that jointly drive tumor growth when their activity is reduced by large heterozygous deletions. In line with our findings, cooperative effects have also been reported from mouse orthologs of human 8p11-p23 genes in a mouse model of HCC. Of note, large 8p deletion, often involving the entire chromosome arm, is one of the most frequent alterations in many solid tumor types including prostate cancer. Moreover, using an “in silico” approach to integrate clinical and molecular data obtained from our large tumor set before, we demonstrate that such cooperative effects are not limited to genes located inside the same deletion, but are also effective in co-deletions located at different chromosomes. Mechanistically, our observations support a model of increasing likelihood for cooperative tumor promoting effects with increasing deletion size, but strongly argue against the concept that one particular tumor suppressor gene drives the development of large deletions. Thus, our findings explain why the “classical” approach of tumor suppressor gene identification in chromosomal regions of deletion, i.e. searching for a gene with a “2nd hit” inside the minimal commonly deletion region, has not been successful in prostate cancer.","[{'e1': ' the size of heterozygous deletions ', 'e2': 'tumor progression ', 'relation': 'greatly correlates with ', 'condition': 'in human prostate cancer'}, {'e1': ' the size of heterozygous deletions ', 'e2': 'tumor aggressiveness', 'relation': 'greatly correlates with ', 'condition': 'in human prostate cancer'}]"
182,P149P4,"Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. National Comprehensive Cancer Network guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening.","[{'e1': 'Presence of intraductal/ductal histology and lymphovascular invasion ', 'e2': 'pathogenic germline DNA-repair gene mutations ', 'relation': 'appear to be associated with ', 'condition': 'in men with prostate cancer'}]"
183,P14P2,"After adjustment for tumor purity for the sequencing data, we observed a significant frequency increase in genomic amplifications and deletions (p = 0.013) and in nonsynonymous point mutations (p = 0.008) with increasing risk group. Interestingly, PGG1 (low risk) was entirely haploid, whereas PGG2–5 exhibited increasing polyploidy frequency. Principal component analysis of genomic profiles revealed that PGG1, PGG2, and PGG3 represent distinct classes, but PGG4 and PGG5 exhibit genomic similarity. Together, these observations for the largest PCa genomic data set to date provide support for increasing genomic alterations with increasing PGG. This is the first genomic correlation of the PGG system. Future work will need to explore the clinical utility of PGGs in prospective studies with long-term follow-up.","[{'e1': ' significant frequency increase ', 'e2': 'genomic amplifications and deletions (p = 0.013) ', 'relation': 'in ', 'condition': 'After adjustment for tumor purity for the sequencing data'}, {'e1': ' significant frequency increase ', 'e2': 'nonsynonymous point mutations (p = 0.008) with increasing risk group', 'relation': 'in ', 'condition': 'After adjustment for tumor purity for the sequencing data'}]"
184,P14P6,"A moderate increase in median prostate-specific antigen (PSA) at diagnosis was observed with increasing risk category (linear regression, p = 0.009), whereas no association with median age at diagnosis was detected (linearregression, p = 0.3189). After adjustment for tumor polyploidy and purity on a sample basis to allow fair comparison across tumors with diverse cellularity, we analyzed tumor genomic characteristics across risk groups. The overall number of nonsynonymous somatic mutations slightly increased across risk strata, reaching higher statistical significance when comparing lower (PGG1 and PGG2) with higher (PGG3, PGG4 and PGG5) risk groups (Wilcoxon-Mann-Whitney test, p = 1.01 104). Overall, more abundant somatic copy number alterations (gains and losses) were observed with increasing PGG.","[{'e1': ' tumor genomic characteristics', 'e2': ' across risk groups', 'relation': 'was analyzed', 'condition': ' After adjustment for tumor polyploidy and purity on a sample basis to allow fair comparison across tumors with diverse cellularity'}]"
185,P14P7,"To investigate aberration frequency across PGGs on a gene basis, we focused on a set of 880 cancer genes. For each aberrant gene we tested possible increasing, decreasing, invariant and mixed (or parabolic) trends (Supplementary material). Examples are shown in Figure 2A, where MYC amplification, TP53 deletion, and 21q22.3 deletion near TMPRSS2 represent increasing, mixed, and invariant frequencies, respectively. Of the 389 recurrently amplified genes (ie, increased somatic DNA copy number) in the data set, 91% exhibit increasing DNA copy number amplification frequency across PGGs; thus, their incidence correlates with higher PGG. This includes NCOA1 (9–50% for PGG1–5) and MYC family members, with MYC reaching the highest frequency in PGG5 (45.5%), followed by MYCN (13.6%) and MYCL (6.8%). A similar situation was observed for 35% of the 756 recurrently deleted genes, whereas a large fraction (56%) exhibited an invariant trend across risk groups (Fig. 2B). Genomic regions with the steepest increase in deletion frequencies across PGGs included areas on 13q32 and 18q21. Interestingly, of the few recurrent somatic point mutations in hormone-naı ̈ve PCa, only TP53 incidence increased across the PGGs (PGG1, 0%; PGG2, 7%; PGG3, 8%; PGG4, 10%, and PGG5, 9%). Complete results for the frequency trend analysis are listed in Supplementary Table 3. There was similar incidence across the groups for the most common aberrations in localized PCa, ERG rearrangement in terms of structural variants and SPOP mutations for single base changes. Frequency trend analysis was also explored for gene aberration within subsets of tumors defined by ERG rearrangement or SPOP mutation. The results are in line with the findings for the whole data set .Consistent with previous studies, while the number of aberrant genes slightly increased with patient age (linear regression using age quartiles, p = 0.027), ERG rearrangement was significantly enriched in the youngest group (58% for the lowest and 32% for the highest age quartile; hypergeometric test, p = 0.0045).","[{'e1': 'a large fraction (56%)', 'e2': 'an invariant trend ', 'relation': ' exhibited ', 'condition': 'across risk groups'}, {'e1': 'Genomic regions ', 'e2': 'deletion frequencies ', 'relation': 'with the steepest increase in ', 'condition': 'across PGGs included areas on 13q32 and 18q21'}]"
186,P151P6,"The level of invasion into FMB is an independent tumor-behavioral factor for PSM and BCR in organ-confined prostate cancer. Patients with a level 2 FMB had a higher risk of BCR after RP. Therefore, the level of invasion into FMB might be used to stratify patients with pT2 disease and a poor prognosis.","[{'e1': 'Patients with a level 2 FMB', 'e2': 'BCR ', 'relation': ' had a higher risk of ', 'condition': 'after RP'}]"
187,P153P1,"The present study aimed to identify potential genes associated with prostate cancer recurrence following radical prostatectomy in order to improve the prediction of the prognosis of patients with prostate cancer. The GSE25136 microarray dataset, including 39 recurrent and 40 non-recurrent prostate cancer samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes were identified using limma packages, and the pheatmap package was used to present the differentially expressed genes screened using a hierarchical cluster analysis. Furthermore, gene ontology functional enrichment analysis was used to predict the potential functions of the differentially expressed genes. Subsequently, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to analyze pathway enrichment of differentially expressed genes in the regulatory network. Lastly, a protein-protein interaction network of the differentially expressed genes was constructed using Cytoscape software to understand the interactions between these differentially expressed genes. A total of 708 differentially expressed genes were identified in the recurrent and non-recurrent prostate cancer samples. Functional annotation revealed that these differentially expressed genes were primarily involved in cell adhesion, negative regulation of growth, and the cyclic adenosine monophosphate and mitogen-activated protein kinase signaling pathways. Furthermore, five key genes, including cluster of differentiation 22, insulin-like growth factor-1, inhibin β A subunit, MAPK kinase 5 and receptor tyrosine kinase like orphan receptor 1, were identified through protein-protein interaction network analysis. The results of the present study have provided novel ideas for predicting the prognosis of patients with prostate cancer following radical prostatectomy.","[{'e1': 'potential genes ', 'e2': 'prostate cancer recurrence ', 'relation': 'is associated with ', 'condition': 'following radical prostatectomy'}]"
188,P153P2,"Prostate cancer, as one of the most common men's malignancy in America, is the second leading cause of cancer-related death in men. Although more than 80% of prostate cancer was diagnosed as localized disease and commonly treated by radical prostatectomy, postoperative recurrence occurred in about 15% of patients within 5 years and up to 40% within 10 years. Recurrence of localized prostate cancer following treatment can lead to lethal metastatic castration-resistant prostate cancer. Various biomarkers have been reported for prostate cancer recurrence surveillance, including preoperative prostate specific antigen value, Gleason score, lymph node invasion and others, but not cancer-specific and inaccurate. Therefore, more efforts should be devoted for identifying disease specific markers of prostate cancer recurrence that can better directly offer practical aid to drug treatment and lead to improved survival and reductions in morbidity.","[{'e1': 'Recurrence of localized prostate cancer ', 'e2': ' lethal metastatic castration-resistant prostate cancer', 'relation': 'can lead to', 'condition': 'following treatment'}]"
189,P153P3,"Although the mechanism underlying prostate cancer is not yet completely understood, multiple genes to help predict prostate cancer risk have been proposed by considerable researches. Brian R. Hu et al reported that AXIN2 expression could not only predict prostate cancer recurrence, but also promoted tumor growth and metastasis in vivo and vitro. Hao et al found that XPO6 expression was elevated in prostate cancer and maybe a potential prognostic biomarker for prostate cancer recurrence. Additionally, some other targets from blood and or urine have been examined and identified, including KLK2-KLK3 SNP rs2735839, 17p12 SNP rs4054823 and Eotaxin-1. However, few of these profiles have been adopted in the clinic after radical prostatectomy to predict recurrent prostate cancer. Therefore, there is still a need for novel tumor biomarkers that can help improve prediction of prostate cancer recurrence upon clinical variables.","[{'e1': 'AXIN2 expression ', 'e2': ' tumor growth ', 'relation': 'promoted', 'condition': 'in vivo and vitro'}, {'e1': 'AXIN2 expression ', 'e2': 'metastasis ', 'relation': 'promoted', 'condition': 'in vivo and vitro'}]"
190,P153P4,"To explore more meaningful molecular biomarker for predicting the prostate cancer prognosis, technologies with high-throughput screen was implied to identify the genes. Microarray data GSE25136 with 39 recurrent and 40 non-recurrent prostate cancer was published and analyzed by Stephenson et al via leave-one-out-cross-validation approach and the results showed that Etoposide-induced 2.4 mRNA and mitogen-activated protein kinase kinase kinase kinase 4 were the most highly overexpressed genes and erythrocyte membrane protein band 4.9 was the most highly underexpressed gene in recurrent tumors compared with primary prostate cancer and may be the potential biomarker. Subsequently, Sun and Goodison conducted a more advanced computational algorithm to analyze the Microarray data GSE25136 and acquire more accurate biomarkers for predicting the prognosis of prostate cancer. With technological development, bioinformatics has been a mainstream tool to analyze the microarray data. In the present study, microarray data GSE25136 was employed to identify differentially expressed genes between prostate cancer and prostate cancer recurrence samples with Limma package in R language. Furthermore, gene ontology and pathway enrichment analysis was performed to screen the differentially expressed genes. Lastly, protein-protein interaction networks of differentially expressed genes was constructed by Cytoscape mapping software and hub genes was identified by the STRING database. Therefore, it is better for us to further understand the molecular mechanisms of prostate cancer.","[{'e1': 'erythrocyte membrane protein band 4.9 ', 'e2': 'underexpressed gene ', 'relation': 'was the most highly ', 'condition': 'in recurrent tumors compared with primary prostate cancer'}]"
191,P154P1,"Using a functional model of breast cancer heterogeneity, we previously showed that clonal subpopulations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient’s primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with L-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.","[{'e1': 'asparagine synthetase expression ', 'e2': 'later metastatic relapse', 'relation': 'was most strongly correlated with ', 'condition': ' in a patient’s primary tumour'}]"
192,P154P16,"EMT-up genes were also downregulated at the transcriptional level in Asns-silenced cells, and they were increased in their RNA levels when these cells were grown in asparagine-supplemented medium. A re-analysis of existing data also showed reduced expression of EMT-up genes when ATF4, which regulates ASNS transcription, was deleted in haploid cells, and liver cells from L-asparaginase-treated ATF4-knockout mice were more perturbed in their EMT program than were similarly treated wild-type mice. Considered together, these data suggest that asparagine bioavailability might affect metastasis, at least in part, through regulation of EMT.","[{'e1': 'EMT-up genes ', 'e2': 'RNA levels ', 'relation': 'were increased in their ', 'condition': 'when these cells were grown in asparagine-supplemented medium'}, {'e1': 'asparagine bioavailability ', 'e2': 'metastasis ', 'relation': 'might affect ', 'condition': 'through regulation of EMT.'}]"
193,P154P18,"Although no differences were detected in haematoxylin and eosin-stained tumour sections, morphological distinctions were noticeable when shRNA-infected 4T1-T cells were isolated from primary tumours by 6-thioguanine selection, with most Asns-silenced cells displaying an epithelial morphology. Most 6-thioguanine-isolated metastatic cells displayed a mesenchymal morphology, regardless of Asns expression status, and this was matched by an increase in the expression of EMT-up genes. Nevertheless, EMT-up genes were downregulated in Asns-silenced versus expressing metastatic cells, indicating an increased representation of epithelial cells in the silenced populations. Similarly, EMT-down genes were upregulated, and Twist and E-cadherin expression measurements indicated a higher epithelial representation in Asns-silenced primary tumour cell populations. These results were validated by qPCR for Twist and E-cadherin in Asns-silenced and expressing cells that were isolated by fluorescence-activated cell sorting from primary and secondary lesions.","[{'e1': 'Twist and E-cadherin expression measurements ', 'e2': 'a higher epithelial representation ', 'relation': 'indicated ', 'condition': 'in Asns-silenced primary tumour cell populations'}]"
194,P154P6,"Of the 11 candidate genes that scored in both the in vitro and in vivo assays, asparagine synthetase had the most robust clinical evidence supporting its relevance to disease progression. Expression levels of the human orthologue, ASNS, were predictive of general and lung-specific relapse in two datasets of patients with breast cancer. Also, when a small collection of matched tumour and lung metastases were transcriptionally profiled, ASNS was found to be more highly expressed in secondary lesions. ASNS is more highly expressed in aggressive tumour subtypes and it is more highly expressed in patients with relapse to the lymph node, brain, liver, and lungs compared with relapse-free survivors. Subsequent analyses identified ASNS as predictive of survival in three additional datasets of patients with breast cancer. In addition to breast tumours, ASNS is negatively correlated with survival in four out of the ten other solid tumours in The Cancer Genome Atlas Pan-Cancer dataset and is a globally predictive biomarker for solid tumours. Previous research has shown that asparagine is an important regulator of cellular metabolism and adaptation.","[{'e1': 'ASNS ', 'e2': 'survival ', 'relation': 'is negatively correlated with ', 'condition': 'in four out of the ten other solid tumours in The Cancer Genome Atlas Pan-Cancer dataset'}]"
195,P155P7,"In this study, we have used next-generation sequencing to obtain detailed gene expression information from different stages of tumour development and progression in two established GEMM of prostate cancer: the PB-Cre/PtenloxP/loxP model, which develops castration-sensitive, invasive but rarely metastasising cancer, and the PB-Cre/p53loxP/loxPRbloxP/loxP model, which develops metastatic castration-resistant prostate cancer. Together, these two models represent useful tools to study both indolent and advanced prostate cancer. Furthermore, deletions and mutations of the tumour suppressors Pten, p53 and Rb are among the most common genomic alterations in human prostate cancer, with two-thirds of prostate cancers showing alterations in at least one of the three genes. We have integrated the genomic data obtained from these models with published human prostate cancer expression data and filtered them for potentially druggable genes. Using this approach, we have identified maternal embryonic leucine zipper kinase (MELK) as a potential therapeutic target in prostate cancer. We have then validated the functional importance of MELK for tumour growth both in vitro and in vivo and identified a new mechanism through which this kinase may drive proliferation and viability of prostate cancer cells.","[{'e1': 'MELK', 'e2': 'a potential therapeutic target', 'relation': 'was identified as', 'condition': 'in prostate cancer'}]"
196,P156P1,"Current diagnostic and prognostic tools for prostate cancer are suboptimal, leading to overdiagnosis and overtreatment. Aberrant promoter hypermethylation of specific genes has been suggested as novel candidate biomarkers for prostate cancer that may improve diagnosis and prognosis. We here analyzed ST6GALNAC3 and ZNF660 promoter methylation in prostate tissues, and ST6GALNAC3, ZNF660, CCDC181, and HAPLN3 promoter methylation in liquid biopsies. First, using four independent patient sample sets, including a total of 110 nonmalignant and 705 prostate cancer tissue samples, analyzed by methylation-specific qPCR or methylation array, we found that hypermethylation of ST6GALNAC3 and ZNF660 was highly cancer-specific with areas under the curve of receiver operating characteristic curve analysis of 0.917–0.995 and 0.846–0.903, respectively. Furthermore, ZNF660 hypermethylation was significantly associated with biochemical recurrence in two radical prostatectomy cohorts of 158 and 392 patients and remained significant also in the subsets of patients with Gleason score ≤7, suggesting that ZNF660 methylation analysis can potentially help to stratify low-/intermediate-grade prostate cancers into indolent vs. more aggressive subtypes. Notably, ZNF660 hypermethylation was also significantly associated with poor overall and prostate cancer-specific survival in the radical prostatectomy cohort with long clinical follow-up available. Moreover, as proof of principle, we successfully detected highly prostate cancer-specific hypermethylated circulating tumor DNA for ST6GALNAC3, ZNF660, HAPLN3, and CCDC181 in liquid biopsies from 27 patients with prostate cancer vs. 10 patients with benign prostatic hyperplasia, using droplet digital methylation-specific PCR analysis. Finally, we generated a three-gene ctDNA hypermethylation model, which detected prostate cancer with 100% specificity and 67% sensitivity. In conclusion, we here for the first time demonstrate diagnostic biomarker potential of ST6GALNAC3 and ZNF660 methylation, as well as prognostic biomarker potential of ZNF660. Furthermore, we show that hypermethylation of four genes can be detected in ctDNA in liquid biopsies from patients with prostate cancer.","[{'e1': 'ZNF660 hypermethylation ', 'e2': 'biochemical recurrence ', 'relation': 'was significantly associated with ', 'condition': 'in two radical prostatectomy cohorts of 158 and 392 patients'}, {'e1': 'ZNF660 hypermethylation ', 'e2': ' poor overall and prostate cancer-specific survival ', 'relation': 'was also significantly associated with', 'condition': 'in the radical prostatectomy cohort with long clinical follow-up available'}]"
197,P156P4,"Aberrant DNA hypermethylation of promoter-associated CpG islands is characteristic for tumor cells, including prostate cancer cells. Promoter hypermethylation is closely associated with gene silencing and may cause downregulation of, for example, tumor suppressor genes during carcinogenesis. Moreover, aberrant promoter hypermethylation of specific genes has been reported to hold promising diagnostic and/or prognostic biomarker potential for prostate cancer in tissue samples. Furthermore, hypermethylation of circulating tumor DNA, which is shed from tumors into the bloodstream as a result of apoptosis, necrosis, and/or active secretion, can be detected in liquid biopsies from patients with prostate cancer, suggesting a promising potential for development of noninvasive or minimally invasive diagnostic tests. So far, only a few candidate promoter methylation markers for prostate cancer have been analyzed in liquid biopsies, including genes known to be frequently hypermethylated in prostate cancer tissue samples, such as GSTP1, APC, RAR2, and CDKN2A. However, whereas the specificity for prostate cancer of these individual candidate markers may be high in liquid biopsies, sensitivity is often suboptimal for diagnostic tests.","[{'e1': 'Promoter hypermethylation ', 'e2': 'tumor suppressor genes ', 'relation': 'may cause downregulation of ', 'condition': 'during carcinogenesis'}, {'e1': 'aberrant promoter hypermethylation of specific genes', 'e2': 'promising diagnostic and/or prognostic biomarker potential ', 'relation': ' has been reported to hold ', 'condition': 'for prostate cancer in tissue samples'}, {'e1': 'hypermethylation of circulating tumor DNA ', 'e2': 'in liquid biopsies ', 'relation': 'can be detected ', 'condition': 'from patients with prostate cancer'}]"
198,P157P2,"The male prostate, as well as early stage prostate cancer, is dependent on androgens activating the androgen receptor for survival, growth, and proliferation. Prostate-specific antigen is a serine protease that is secreted from the prostate and is transcriptionally regulated by androgen receptor. Thus, along with digital rectal exams, prostate-specific antigen-based screening is routinely used for early detection of prostate cancer, although the magnitude of benefit from prostate-specific antigen screening continues to be debated. Biopsies are typically done to confirm prostate cancer, and if diagnosed with clinically significant disease, a patient most commonly has external beam radiation therapy or radical prostatectomy. Adjuvant androgen deprivation with radiation or adjuvant radiation after surgery may be administered in the setting of tumors with high risk of recurrence. Androgen deprivation therapy that suppresses testicular function is typically first-line therapy for androgen-sensitive prostate cancer. A small additional survival benefit may be seen when first-generation oral androgen receptor inhibitors such as bicalutamide and flutamide are combined with androgen deprivation therapy. Initial positive response to androgen deprivation therapy is common by evidence of decline prostate-specific antigen levels in 90% of patients and duration of response to therapy varies, with 5–10% of patients surviving 10 years after initiating androgen deprivation therapy. In two recent phase III clinical trials, hormone naive patients with locally advanced or oligometastatic disease starting first-line long-term androgen deprivation therapy treatment were also given abiraterone acetate and prednisone. Abiraterone acetate is a potent, second-generation inhibitor that blocks androgen synthesis, significantly decreasing circulating androgen below levels achieved with testicular suppression alone. In the STAMPEDE trial, inclusion of abiraterone acetate early in the treatment protocol resulted in a lower risk of death by 37%. The 3-year survival rate was 76% with standard androgen deprivation therapy treatment alone and 83% with the standard care in combination with abiraterone acetate as well as a 14-month failure-free survival advantage. The results were also verified in a separate LATITUDE trial. In another phase III clinical trial, patients with hormone-sensitive metastatic prostate cancer were given docetaxel in combination with first-line androgen deprivation therapy treatment. The median overall survival with combination treatment was 13.6 months longer than with androgen deprivation therapy alone, nearly identical to the STAMPEDE and LATITUDE trials. A decrease in prostate-specific antigen to less than 0.2 ng/ml at 12 months was 27.7% for the combination group compared to 16.8% for the androgen deprivation therapy only group, and the median time for development of castration-resistant prostate cancer was increased. The results of these exciting clinical trials have prompted earlier use of docetaxel or abiraterone acetate plus standard androgen deprivation therapy to delay time of metastatic castration-resistant prostate cancer and ultimately death.","[{'e1': ' inclusion of abiraterone acetate early in the treatment protocol ', 'e2': 'a lower risk of death by 37%', 'relation': 'resulted in ', 'condition': 'In the STAMPEDE trial'}]"
199,P157P3,"Metastatic castration-resistant prostate cancer is associated with poor prognosis with a mean survival time of 16–18 months. The U.S. Food and Drug Administration-approved therapies for metastatic castration-resistant prostate cancer include chemotherapy agents, second-generation hormonal therapies, immunotherapy, and radium-223. Androgen receptor point mutations and amplifications have led to resistance to first-line androgen deprivation therapy treatments, and since androgen receptor remains active in metastatic castration-resistant prostate cancer, these patients respond to abiraterone acetate and enzalutamide, but with a modest increase in overall survival of 3–4 months. A major resistance mechanism to abiraterone acetate and enzalutamide involve the presence of androgen receptor splice variants, such as ARv7, possibly explaining the modest overall survival benefit of these agents in an unselected population. Androgen receptor splice variants are truncated forms of wild-type androgen receptor where the ligand-binding domain is lost, activation is ligand independent, and these variants are constitutively active. It was recently shown that ARv7 mRNA detection in circulating tumor cells correlated with poor outcomes in patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate and enzalutamide. It is still unclear if androgen receptor splice variants are functionally contributing to treatment resistance, but ARv7 has developed into an important predictive biomarker for metastatic castration-resistant prostate cancer patients taking either abiraterone acetate or enzalutamide. Another result of resistance to prolonged administration of abiraterone acetate and enzalutamide is the development of a lethal variant of metastatic castration-resistant prostate cancer termed aggressive variant prostate cancer. Indeed, aggressive variant prostate cancer was classified in 15% of metastatic castration-resistant prostate cancers prior to the approval of abiraterone acetate and enzalutamide; however, this population shifted to 31% aggressive variant prostate cancer post-abiraterone acetate and enzalutamide. Several great reviews have been written on this disease variant, and recent work has classified aggressive variant prostate cancer into two distinct subtypes: androgen receptor-null expressing neuroendocrine differentiation markers and androgen receptor-null lacking markers of neuroendocrine differentiation. Aggressive variant prostate cancer is characterized by several clinical and genetic features to include low prostate-specific antigen and androgen receptor protein expression, loss of retinoblastoma, TP53 mutations, overexpression of Aurora kinase A, and amplification of N-Myc. Survival is typically less than a year with limited treatment options to include platinum-based chemotherapy. Based on the recent literature, it is becoming apparent that androgen receptor-independent pathways such as activated MAPK and FGFR kinase pathways are responsible for aggressive variant prostate cancer development and progression. Indeed, several clinical trials investigating androgen receptor-independent pathways are underway in prostate cancer including agents that target MEK and/or SRC, Aurora kinase A, PI3K/mammalian target of rapamycin, and DNAPK, although not all of these trials focus on aggressive variant prostate cancer.","[{'e1': 'ARv7 mRNA detection in circulating tumor cells', 'e2': ' poor outcomes ', 'relation': ' correlated with', 'condition': 'in patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate and enzalutamide'}, {'e1': 'aggressive variant prostate cancer ', 'e2': '15% of metastatic castration-resistant prostate cancers', 'relation': 'was classified in ', 'condition': ' prior to the approval of abiraterone acetate and enzalutamide'}]"
200,P157P4,"The treatment landscape of metastatic castration-resistant prostate cancer and aggressive variant prostate cancer involve several one-size-fits-all approaches with no real stratification of patients or novel targeted therapies, with a few emerging exceptions. The observation that androgen receptor amplification and missense mutations are observed in nearly 70% of metastatic castration-resistant prostate cancer cases has led to the clinical paradigm where all patients are essentially treated with some form of androgen synthesis or androgen receptor function inhibitors. Other genetic alterations have been observed at high frequency in metastatic castration-resistant prostate cancer patients but are not yet predictive for any particular targeted therapy. Recent whole-genome and transcriptome sequencing efforts have identified several genetic aberrations in metastatic castration-resistant prostate cancer patients at lower frequency to include TP53, RB1, PIK3CA/B, BRAF/RAF1, BRCA2, BRCA1, and ATM. In another study, the exomes of over 100 primary prostate adenocarcinomas and normal tissue pairs were sequenced and led to the identification of new recurrent mutations including MED12, FOXA1, and SPOP. It was later shown that recurrent point mutations in SPOP in prostate cancer activates the PI3K/AKT/mTOR and androgen receptor signaling pathways providing functional evidence that this mutation may serve as a predictive biomarker to PI3K or AKT inhibitors in combination with antiandrogens.","[{'e1': ' recurrent point mutations in SPOP', 'e2': 'PI3K/AKT/mTOR ', 'relation': 'activates the ', 'condition': ' in prostate cancer '}]"
201,P158P3,"HDDA10 showed significant performance for predicting metastasis and biochemical recurrence in the validation set, outperforming Gleason grade grouping for biochemical recurrence and with comparable performance for metastasis endpoint. HDDA10 prognostic significance was superior to any clinical–pathological parameter within grade group 2 and 3 patients for biochemical recurrence and also performed better for metastasis than Gleason pattern 4. HDDA10 remained significant for both biochemical recurrence and metastasis in multivariate analysis, suggesting that it can be used to increase accuracy in stratifying patients eligible for active surveillance.","[{'e1': 'HDDA10', 'e2': 'metastasis and biochemical recurrence ', 'relation': ' showed significant performance for predicting ', 'condition': 'in the validation set'}, {'e1': 'HDDA10 ', 'e2': 'both biochemical recurrence and metastasis ', 'relation': 'remained significant for ', 'condition': 'in multivariate analysis'}]"
202,P159P7,"In conclusion, there are now two systemic therapies, DocP and AAP, which have shown a survival benefit from RCTs when added to treatment of patients starting long-term ADT for the first time. The evidence from our directly randomised data comparing these two therapies showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events, suggesting that both currently remain viable new standards-of-care.","[{'e1': ' DocP and AAP ', 'e2': 'RCTs ', 'relation': 'have shown a survival benefit from ', 'condition': 'when added to treatment of patients starting long-term ADT for the first time'}]"
203,P15P1,"Patients with clinically insignificant prostate cancer remain a major over-treated population. PTEN loss is one of the most recurrent alterations in prostate cancer associated with an aggressive phenotype; however, the occurrence of PTEN loss in insignificant prostate cancer has not been reported and its role in the separation of insignificant from significant prostate cancer is unclear. An integrated analysis of PTEN loss was, therefore, performed for structural variations, point mutations and protein expression in clinically insignificant (48 cases) and significant (76 cases) prostate cancers treated by radical prostatectomy. Whole-genome mate pair sequencing was performed on tumor cells isolated by laser capture microdissection to characterize PTEN structural alterations. Fluorescence in situ hybridization probes were constructed from the sequencing data to detect the spectrum of these PTEN alterations. PTEN loss by mate pair sequencing and fluorescence in situ hybridization occurred in 2% of insignificant, 13% of large volume Gleason score 6, and 46% of Gleason score 7 and higher cancers. In Gleason score 7 cancers with PTEN loss, PTEN alterations were detected in both Gleason pattern 3 and 4 in 57% of cases by mate pair sequencing, 75% by in situ hybridization and 86% by immunohistochemistry. PTEN loss by sequencing was strongly associated with TMPRSS2-ERG fusion, biochemical recurrence, PTEN loss by in situ hybridization and protein loss by immunohistochemistry. The complex nature of PTEN rearrangements was unveiled by sequencing, detailing the heterogeneous events leading to homozygous loss of PTEN. PTEN point mutation was present in 5% of clinically significant tumors and not in insignificant cancer or high-grade prostatic intraepithelial neoplasia. PTEN loss is infrequent in clinically insignificant prostate cancer, and is associated with higher grade tumors. Detection of PTEN loss in Gleason score 6 cancer in a needle biopsy specimen indicates a higher likelihood of clinically significant prostate cancer.","[{'e1': 'PTEN loss ', 'e2': 'recurrent alterations ', 'relation': 'is one of the most ', 'condition': 'in prostate cancer associated with an aggressive phenotype'}, {'e1': 'An integrated analysis of PTEN loss ', 'e2': ' structural variations ', 'relation': 'was performed for', 'condition': 'in clinically insignificant (48 cases) prostate cancers treated by radical prostatectomy.'}, {'e1': 'An integrated analysis of PTEN loss ', 'e2': 'point mutations', 'relation': 'was performed for', 'condition': 'in clinically insignificant (48 cases) prostate cancers treated by radical prostatectomy.'}, {'e1': 'An integrated analysis of PTEN loss ', 'e2': 'protein expression ', 'relation': 'was performed for', 'condition': 'in clinically insignificant (48 cases) prostate cancers treated by radical prostatectomy.'}, {'e1': 'An integrated analysis of PTEN loss ', 'e2': ' structural variations ', 'relation': 'was performed for', 'condition': 'in clinically significant (76 cases) prostate cancers treated by radical prostatectomy.'}, {'e1': 'An integrated analysis of PTEN loss ', 'e2': 'point mutations', 'relation': 'was performed for', 'condition': 'in clinically significant (76 cases) prostate cancers treated by radical prostatectomy.'}, {'e1': 'An integrated analysis of PTEN loss ', 'e2': 'protein expression ', 'relation': 'was performed for', 'condition': 'in clinically significant (76 cases) prostate cancers treated by radical prostatectomy.'}, {'e1': 'PTEN alterations ', 'e2': 'both Gleason pattern 3 and 4 ', 'relation': 'were detected in ', 'condition': 'in 57% of cases by mate pair sequencing'}, {'e1': 'PTEN alterations ', 'e2': 'both Gleason pattern 3 and 4 ', 'relation': 'were detected in ', 'condition': 'in 75% of cases by situ hybridization '}, {'e1': 'PTEN alterations ', 'e2': 'both Gleason pattern 3 and 4 ', 'relation': 'were detected in ', 'condition': 'in 86% of cases by immunohistochemistry'}]"
204,P15P3,"As PTEN loss is associated with aggressive prostate cancer, it could potentially have a role in separating patients that have significant prostate cancer from those with insignificant cancer. However, there remain important questions in regards to PTEN deletion and mutation and risk of prostate cancer significance and progression. Although PTEN deletion is reported in Gleason score 6 and confined prostate cancer, the frequency of PTEN mutation and deletion is unknown in insignificant prostate cancer (defined in radical prostatectomy specimens as tumors that are Gleason score 6, confined, and tumor volume <0.5 cm3). In addition, recent studies of contemporary Gleason grading and studies of Gleason score 6 cancer and outcome following surgery suggest that studies have potentially overestimated the frequency of PTEN deletion in Gleason score 6 cancer by under-grading Gleason score 7 and higher grade cancers. Recently the presence of PTEN protein loss in Gleason score 6 needle biopsy specimens has been associated with increased likelihood of Gleason score upgrading in radical prostatectomy specimens. Understanding the relationship of PTEN loss, cancer significance, and the relationship of Gleason pattern 3 and Gleason pattern 4 in regards to shared PTEN alterations in Gleason score 7 and higher cancer has important implications in the assessment of prostate needle biopsy specimens where only a small portion of a tumor is sampled.","[{'e1': 'studies ', 'e2': 'the frequency of PTEN deletion ', 'relation': 'have potentially overestimated ', 'condition': 'in Gleason score 6 cancer by under-grading Gleason score 7 and higher grade cancers'}, {'e1': 'the presence of PTEN protein loss in Gleason score 6 needle biopsy specimens ', 'e2': 'increased likelihood of Gleason score upgrading ', 'relation': 'has been associated with ', 'condition': 'in radical prostatectomy specimens'}]"
205,P15P4,"The primary objectives of this study were to characterize the PTEN status in insignificant and significant prostate cancer from radical prostatectomy specimens using whole-genome mate pair sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry to determine the frequency of PTEN abnormalities in insignificant and significant prostate cancer including structural alterations and mutations. The additional objective was to understand the relationship of Gleason pattern 3 and Gleason pattern 4 in Gleason score 7 cancers in regard to PTEN loss to determine if understanding PTEN status could have a role in determining prostate cancer significance and stratifying risk of progression in newly diagnosed prostate cancer patients.","[{'e1': ' understanding PTEN status ', 'e2': 'in determining prostate cancer significance and stratifying risk of progression ', 'relation': 'could have a role ', 'condition': 'in newly diagnosed prostate cancer patients.'}]"
206,P160P6,"The most promising phenes identified in this study have been investigated regarding their biological plausibility and turned out to agree well with previous findings as described in literature. For example, the top-ranking phene “RATIO #CD8_border1 TO #CD34_border1” suggests that a high ratio of areas of CD8(+) cells and CD34(+) microvessels in the tight tumor border are correlated with a good prognosis and long-term disease-free survival. This corresponds to high densities of CD8(+) cells and/or low microvessel densities, which as separate properties have been shown to be associated with good prognosis in prostate cancer in the literature. The second-best phene “DIST CD68 TO CD34 IN nonIntact” which is also closely related to the 6th-ranked “RATIO #CD68_border2 TO #CD34_border1” as well includes the microvessel density in the tumor region, stating that larger distance of CD68(+) macrophages to microvessels or a high density of CD68(+) macrophages together with a low microvessel density point to a good prognosis. Again, a low microvessel density seems to be beneficial as well as a higher density of CD68(+) macrophages. This corresponds well to the 4th-ranked phene “RATIO #CD8_nonIntact TO #CD163_nonIntact” where a high density of CD8(+) and importantly a low density CD163(+) relate to a good prognosis. Finally, also the mixture pattern of differently-sized non-cancerous and cancerous glands provides prognostic value as shown by the 3rd-ranked phene “CORR Haralick on intact & non-intact glands”. Here, a low linear dependency between glands of different types relates to cases without tumor progression. This to a certain degree reflects and refines the criteria used for Gleason scoring by systematically quantifying glandular patterns. Current limitations of the prostate study include the moderate size of the study population (90 patients), the lack of an independent validation cohort from a different clinical site, as well as the limited length of the follow-up times for certain patients. In future work we are aiming to improve on these limitations, in particular, to test our findings on an additional patient cohort. Also, we will validate the prognostic phenes we identified in whole slide images from resected prostate tissue in fine needle biopsies. If similar patterns of the immunological landscape are observed also in needle biopsies Tissue Phenomics will directly improve critical treatment decision in prostate cancer patients, for example, avoiding an unnecessary surgery, particularly in the case of intermediate risk patients. Finally, also in the context of immunotherapies Tissue Phenomics offers large potential to better stratify patients for the treatment options currently available for prostate cancer.","[{'e1': 'high densities of CD8(+) cells ', 'e2': 'good prognosis ', 'relation': 'has been shown to be associated with ', 'condition': 'in prostate cancer in the literature'}, {'e1': ' low microvessel densities ', 'e2': 'good prognosis ', 'relation': 'has been shown to be associated with ', 'condition': 'in prostate cancer in the literature'}]"
207,P161P1,"Solute carrier organic anion (SLCO) gene families encode organic anion transport proteins, which are transporters that up-take a number of substrates including androgens. Among them, high expression of SLCO2B1 is known to associate with the resistance to androgen deprivation therapy in prostate cancer (PCa). We hypothesized that high expression of SLCO genes enhances PCa progression by promoting the influx of androgen. Here, we demonstrated the impact of the expression levels of SLCO2B1 on prognosis in localized PCa after radical prostatectomy (RP) utilizing 494 PCa cases in The Cancer Genome Atlas (TCGA). SLCO2B1 high expression group showed significantly worse Disease-free survival (DFS) after RP (p = 0.001). The expression level of SLCO2B1 was significantly higher in advanced characteristics including Gleason Score (GS ≤ 6 vs GS = 7; p = 0.047, GS = 7 vs GS ≥ 8; p = 0.002), pathological primary tumor (pT2 vs pT3/4; p < 0.001), and surgical margin status (positive vs negative; p = 0.013), respectively. There was a significant difference in DFS between these two groups only in GS ≥ 8 patients (p = 0.006). Multivariate analysis demonstrated that only SLCO2B1 expression level was an independent predictor for DFS after RP in GS ≥ 8. SLCO2B1 high expressed tumors in GS ≥ 8 not only enriched epithelial mesenchymal transition (EMT) related gene set, (p = 0.027), as well as Hedgehog (p < 0.001), IL-6/JAK/STAT3 (p < 0.001), and K-ras signaling gene sets (p < 0.001), which are known to promote EMT, but also showed higher expression of EMT related genes, including N-cadherin (p = 0.024), SNAIL (p = 0.001), SLUG (p = 0.001), ZEB-1 (p < 0.001) and Vimentin (p < 0.001). In conclusion, PCa with high expression of SLCO2B1 demonstrated worse DFS, which might be due to accelerated EMT.","[{'e1': ' high expression of SLCO2B1 ', 'e2': 'the resistance to androgen deprivation therapy ', 'relation': 'is known to associate with ', 'condition': 'in prostate cancer (PCa)'}, {'e1': ' high expression of SLCO genes ', 'e2': 'PCa progression ', 'relation': 'enhances ', 'condition': 'by promoting the influx of androgen'}, {'e1': 'SLCO2B1 high expression group ', 'e2': 'worse Disease-free survival (DFS) ', 'relation': 'showed significantly ', 'condition': 'after RP (p = 0.001)'}, {'e1': 'SLCO2B1 expression level ', 'e2': ' DFS ', 'relation': 'was an independent predictor for', 'condition': 'after RP in GS ≥ 8'}]"
208,P161P4,"Solute carrier organic anion (SLCO) gene families encode organic anion transport proteins (OATP), which are membrane transporters widely expressed in the human body that influx numerous compounds and drugs including androgens. Several investigations have shown that SLCO genes, SLCO2B1 and SLCO1B3, mediate the uptake of androgen into PCa cells. SLCO2B1 transports one of the adrenal androgens, dehydroepiandrosterone sulfate (DHEAS), which is a precursor to the most potent androgen receptor into normal prostate and PCa cell. SLCO2B1 expression levels have been shown to correlate with DHEAS uptake in PCa cell lines. On the other hand, SLCO1B3 transports testosterone, which is essential for progression of PCa. In agreement, the expression of these genes has been shown to be associated with the resistance to androgen deprivation therapy, which is the standard treatment for PCa. SLCO2B1 has been shown to be significantly increased in metastatic tissue, compared to primary tissue in PCa, and polymorphisms of SLCO2B1 gene is associated with shorter time to progression and overall survival (OS) in patients with metastatic PCa receiving androgen deprivation therapy. These findings suggest that SLCO2B1 expression is associated with the progression of PCa.","[{'e1': 'SLCO2B1 expression levels', 'e2': 'DHEAS uptake ', 'relation': ' have been shown to correlate with ', 'condition': 'in PCa cell lines'}, {'e1': 'polymorphisms of SLCO2B1 gene ', 'e2': 'shorter time to progression ', 'relation': 'is associated with ', 'condition': 'in patients with metastatic PCa receiving androgen deprivation therapy'}, {'e1': 'polymorphisms of SLCO2B1 gene ', 'e2': 'overall survival (OS) ', 'relation': 'is associated with ', 'condition': 'in patients with metastatic PCa receiving androgen deprivation therapy'}]"
209,P161P5,"However, the significance of SLCO2B1 gene expression on the recurrence after RP in PCa has not been investigated. We hypothesized that the expression level of SLCO genes will affect the progression of PCa and lead micro-metastasis by promoting the influx of androgen. In the present study, we investigated the impact of the expression level of SLCO2B1 on patient survival in localized PCa who underwent RP.","[{'e1': ' the expression level of SLCO genes ', 'e2': 'the progression of PCa and lead micro-metastasis ', 'relation': 'will affect ', 'condition': 'by promoting the influx of androgen'}]"
210,P161P6,"In conclusion, PCa with high expression of SLCO2B1 in high GS tumors demonstrated worse DFS, which might be due to accelerated EMT. Further studies are needed to determine the clinical application of SLCO2B1 levels.","[{'e1': 'PCa with high expression of SLCO2B1 ', 'e2': 'worse DFS', 'relation': 'demonstrated ', 'condition': 'in high GS tumors '}]"
211,P163P10,"PSA is commonly used as a tumour biomarker after RP in order to identify possible recurrences. Early (< 3 year) biochemical failure was identified as a significant predictor of metastatic progression and cancer related death, thus representing a useful marker in the clinical practice. We expect an improvement of early biochemical failure in the study arm compared to the control arm. The prognostic value of PSA nadir to predict PCa survival after 3 months of hormonal treatment and before EBRT was tested. PSA levels < 0.5 ng/ml can predict patient survival and this observation was also confirmed recently for PSA levels ≤ 0.3 ng/ml. PSA nadir before EBRT is, thus, an important biomarker of hormonal response and also a predictor of survival in this setting.","[{'e1': 'PSA ', 'e2': ' a tumour biomarker', 'relation': 'is commonly used as', 'condition': ' after RP'}]"
212,P163P11,"Novel imaging techniques are expected to overcome the problem of invasive sample collection in the near future by allowing accurate diagnosis, tumour staging and assessment of treatment response. Positron emission tomography (PET) is a recognized tool to detect tumour lesions by targeting their metabolic activity or their specific antigen expression. PSMA (prostate specific membrane antigen) is a type II trans-membrane protein that is specifically expressed on the surface of PCa cells and could be used as a tracer to investigate anti-androgen response. PSMA can be targeted by a PSMA-ligand associated to 68Gallium. This tracer has been implemented in PET-computed tomography (PET-CT) for the detection of PCa in the metastatic setting. There is also evidence of PSMA regulation by androgens. Immunohistochemical examination of FFPE (formalin fixed paraffin embedded) PCa tissues of patients treated by different anti-androgen therapies showed an over-expression of PSMA after therapy in 55% of primary tumour samples and 100% of metastatic lesions compared to the baseline. Thus, a better insight on PSMA expression in castration naïve patients following new generation ADT is of interest. Recently, PET/MR hybrid imaging has been introduced next to PET/CT in order to allow the combination of specific properties of different imaging techniques. 68Ga-PSMA PET demonstrated high potential to detect minimal PCa lesions. In preliminary studies, hybrid 68Ga-PSMA PET/MR technology has demonstrated to be promising in the diagnosis and follow up of PCa. The same imaging technology might also represent an important improvement for treatment follow-up. The neoadjuvant setting offers an ideal platform to study this hypothesis.","[{'e1': 'Immunohistochemical examination of FFPE (formalin fixed paraffin embedded) PCa tissues of patients treated by different anti-androgen therapies ', 'e2': 'over-expression of PSMA ', 'relation': 'showed an ', 'condition': 'after therapy in 55% of primary tumour samples and 100% of metastatic lesions compared to the baseline'}]"
213,P163P13,"Preoperative treatment provides a platform to evaluate pharmacodynamics endpoints of novel agents and enable the identification of signals of biologic activity. In addition, it may allow for the identification of molecular and biologic prognostic and predictive factors. In this respect, some promising but mainly preclinical data have been reported on the relationship between androgen receptor signalling and DNA damage response pathways. We wish to explore this field through IHC, transcriptome analyses and genome analysis. We chose DNA-PKcs and PARP1 as target proteins for IHC because androgens can activate their transcription. DNA-PKcs is implicated in double strand break (DSB) repair. PARP1 is a nuclear enzyme implicated in DNA repair, tumour proliferation and mediation of androgen receptor-DNA interaction. It can activate the DNA repair process. The therapeutic potential of PARP1 inhibitors has been tested in an explant system of primary human tumours, showing that inhibiting PARP1 enzyme leads to a decrease in tumour proliferation. TOPARP-A (The Trial of PARP Inhibition in Prostate Cancer) phase 2 trial studied the PARP inhibitor olaparib in mCRPC patients showing good response rates particularly for BRCA1/2 or ATM gene-mutated tumours that justified the breakthrough therapy designation by FDA (Food and Drug Administration).","[{'e1': ' inhibiting PARP1 enzyme ', 'e2': 'a decrease in tumour proliferation', 'relation': 'leads to ', 'condition': ' in an explant system of primary human tumours'}]"
214,P163P6,"Neoadjuvant therapy is routinely utilized for the treatment of muscle invasive bladder, esophageal and rectal cancer with the scope of down-staging the primary tumour and control of possible micro-metastatic clones. In this context, neoadjuvant therapy before radical prostatectomy is an interesting possibility in particular for intermediate and high-risk disease. PCa has the peculiarity to be largely dependent on androgen regulation, a mechanism that is routinely targeted in advanced cases. Neoadjuvant hormonal therapy using luteinizing hormone releasing hormone (LHRH) agonists and/or antiandrogens has already demonstrated to downstage primary PCa, however, there is a lack of survival data especially for patients with high-risk disease, considering that the previous controlled trials generally assessed low-intermediate risk patients with various ADT regimens and relatively short follow ups. Recently it was suggested that neoadjuvant ADT could decrease cancer related death in high-risk patients, especially when adjuvant EBRT is associated. Considering the increasing availability of new generation androgen receptor pathway inhibitors, there is a new wave of studies that are assessing the anti-tumour effect of these compounds on the primary tumour using pathologic characteristics (pathologic complete response, minimal residual disease) as proxy of an anti-tumour effect. Degarelix is a well-known LHRH antagonist that is commonly used in advanced prostate cancer, with the advantage that it avoids tumour flare-up with a faster depression of testosterone levels compared to LHRH agonists. It was shown that degarelix is not inferior to goserelin + bicalutamide in decreasing the prostate volume in PCa patients, thus it was suggested to be a valuable alternative in the neoadjuvant setting. Degarelix was recently studied before prostatectomy but the results were controversial, showing higher intra-tumour levels of dihydrotestosterone compared to LHRH agonist + bicalutamide or degarelix + bicalutamide, generating the hypothesis of unknown mechanisms of action that should be better analyzed in other trials. Interestingly, pathological complete response was obtained for degarelix when it was associated with bicalutamide, generating the hypothesis that a stronger androgen blockade can result in a stronger anti-tumour effect. Degarelix was compared to leuprolide in the pivot trial CS21 in hormone sensitive patients showing a sustained testosterone suppression with improved PSA progression-free survival for degarelix compared to LHRH analogue. In the extension phase, those patients who crossed-over from leuprolide to degarelix, experienced an improved PSA response and progression-free survival supporting the better effect of the LHRH antagonist. Neoadjuvant studies, in the surgical setting, are also a unique opportunity to complete our knowledge on mechanisms of action and molecular response to such new generation of compounds. Apalutamide (alias ARN-509) is a second-generation antiandrogen with a pure antagonist mechanism with 7–10 fold higher affinity with the androgen receptor compared to bicalutamide. It is currently studied in phase III trials for treatment of castration naïve or castration resistant PCa. The possibility to study the anti-tumour effect of the complete androgen blockade based on apalutamide + degarelix is of interest, considering the safety profile of these compounds and potential benefit for the patients.","[{'e1': ' neoadjuvant ADT', 'e2': 'cancer related death ', 'relation': ' could decrease ', 'condition': 'in high-risk patients, especially when adjuvant EBRT is associated'}]"
215,P163P7,"The therapeutic effect of EBRT is mediated by DNA damage and hence the DNA repair mechanisms are the leading mechanisms in radio-resistance. In preclinical studies, even in the absence of radiation, antiandrogens induce an increased DNA damage and decreased DNA repair in PCa cell lines. Thus, DNA repair is androgen dependent in cell lines, but a better insight in these mechanisms in localized tumour tissue and the assessment of possible novel therapies to decrease the activity of DNA repair mechanisms could help understanding and optimizing treatment modalities. We hypothesize that ARN-509 in combination with degarelix can inhibit DNA repair mechanism more intensively than classic hormonal treatment.","[{'e1': 'antiandrogens ', 'e2': 'an increased DNA damage ', 'relation': 'induce ', 'condition': 'in PCa cell lines'}, {'e1': 'antiandrogens ', 'e2': 'a decreased DNA repair ', 'relation': 'induce ', 'condition': 'in PCa cell lines'}]"
216,P163P9,"Second generation androgen receptor pathway inhibitors can induce resistance through different mechanisms. One of these mechanisms is the expression of androgen receptor splice variants. More specifically, the ARV7 variant was found to be a marker for second-generation antiandrogen resistance in mCRPC. There is a lack of data about ARV7 expression in primary PCa. Recently it was demonstrated that ARV7 can be expressed in patients treated with degarelix + bicalutamide + abiraterone + prednisolone before prostatectomy but this was not related to the therapy response.","[{'e1': 'Second generation androgen receptor pathway inhibitors ', 'e2': 'resistance ', 'relation': 'can induce ', 'condition': 'through different mechanisms'}, {'e1': 'the ARV7 variant ', 'e2': 'second-generation antiandrogen resistance ', 'relation': 'was found to be a marker for ', 'condition': 'in mCRPC'}]"
217,P165P10,PTEN loss is associated with significant changes in tumor methylation profiles and contributes to aggressive prostate cancer and recurrence.,"[{'e1': 'PTEN loss ', 'e2': 'significant changes', 'relation': 'is associated with ', 'condition': ' in tumor methylation profiles'}]"
218,P165P6,"PTEN loss in prostate cancer is associated with aggressive disease and poor prognosis, often co-occurring with TMPRSS2:ERG gene fusion, suggesting cooperative tumorigenesis.","[{'e1': 'PTEN loss ', 'e2': 'aggressive disease ', 'relation': 'is associated with ', 'condition': 'in prostate cancer'}, {'e1': 'PTEN loss ', 'e2': 'poor prognosis', 'relation': 'is associated with ', 'condition': 'in prostate cancer'}]"
219,P167P6,"Combined with previous studies, a picture of the life-history of aggressive prostate cancer is beginning to emerge. Tumors start with slow gradual accumulation of SNVs, punctuated by deletion of some tumor suppressors. In a subset of tumors, driver mutations or other phenomenon induce a switch to the rapid accumulation of copy number gains. These driver mutations lead to changes in the set of active mutational processes, particularly increased homologous recombination deficiency even in early localized disease. Concomitant evolutionary branching create subclonal diversity, and a subset of these subclones survive primary, definitive therapy, either at the original site or as occult metastases. The surviving tumor subclones expand to form a network of related clones that colonize, compete, and collaborate across multiple metastatic sites. However, this broad life history hides large inter-tumoral differences in driver genes, mutagenic processes, and clinical aggressivity. Moving forward, it will be key to develop very large, clinically well-annotated patient cohorts that will allow mechanistic insight into the specific clinical implications of different subclonal driver architectures and mutational processes.","[{'e1': ' driver mutations or other phenomenon', 'e2': 'a switch to the rapid accumulation of copy number gains', 'relation': ' induce ', 'condition': ' In a subset of tumors'}]"
220,P167P7,"Overall, this life history of prostate cancer implies that early identification of tumors with multiple subclones and aggressive genomic and epigenomic features will improve cure rates through personalized therapy. These patients with highly aggressive tumors may benefit from adjuvant systemic treatment to prevent failure from occult metastatic disease. By contrast, our data provocatively suggest that patients with monoclonal tumors who are intermediate risk based on NCCN criteria could be studied for inclusion in trials of active surveillance.","[{'e1': 'early identification of tumors with multiple subclones and aggressive genomic and epigenomic features ', 'e2': ' cure rates', 'relation': 'will improve', 'condition': ' through personalized therapy'}]"
221,P168P1,"Single nucleotide polymorphisms (SNPs) within the regulatory elements of a gene can alter gene expression, making these SNPs of prime importance for candidate gene association studies. We aimed to determine whether such regulatory variants are associated with clinical outcomes in three cohorts of patients with prostate cancer. We used RegulomeDB to identify potential regulatory variants based on in silico predictions and reviewed genome-wide experimental findings. Overall, 131 putative regulatory SNPs with the highest confidence score on predicted functionality were investigated in two independent localized prostate cancer cohorts totalling 458 patients who underwent radical prostatectomy. The statistically significant SNPs identified in these two cohorts were then tested in an additional cohort of 504 patients with advanced prostate cancer. We identified one regulatory SNP, rs1646724, that was consistently associated with increased risk of recurrence in localized disease and mortality in patients with advanced prostate cancer after adjusting for known clinicopathological factors. Further investigation revealed that rs1646724 may affect expression of SLC35B4, which encodes a glycosyltransferase, and that down-regulation of SLC35B4 by transfecting short hairpin RNA in DU145 human prostate cancer cell suppressed proliferation, migration and invasion. Furthermore, we found increased SLC35B4 expression correlated with more aggressive forms of prostate cancer and poor patient prognosis. Our study provides robust evidence that regulatory genetic variants can affect clinical outcomes.","[{'e1': ' rs1646724 ', 'e2': ' increased risk of recurrence', 'relation': 'was consistently associated with', 'condition': ' in localized disease '}, {'e1': ' rs1646724 ', 'e2': 'mortality', 'relation': 'was consistently associated with', 'condition': ' in patients with advanced prostate cancer '}, {'e1': ' rs1646724 ', 'e2': ' increased risk of recurrence in localized disease ', 'relation': 'was consistently associated with', 'condition': 'after adjusting for known clinicopathological factors'}, {'e1': ' rs1646724 ', 'e2': 'mortality in patients with advanced prostate cancer ', 'relation': 'was consistently associated with', 'condition': 'after adjusting for known clinicopathological factors'}]"
222,P169P10,"Biochemical recurrence affects a significant proportion of men after they undergo definitive treatment for prostate cancer. Approximately 20% to 40% of men who undergo radical prostatectomy and 30% to 50% of men who undergo radiation therapy will develop biochemical recurrence within 10 years after treatment, and nearly two-thirds of these cases occur within the first two years. Men with biochemical recurrence have a higher risk of metastatic disease and death from prostate cancer progression compared to those without biochemical recurrence. Therefore, predicting which men will develop biochemical recurrence could allow for early identification of patients who might benefit from adjuvant therapy.","[{'e1': 'Biochemical recurrence ', 'e2': 'a significant proportion of men ', 'relation': 'affects ', 'condition': 'after they undergo definitive treatment for prostate cancer'}, {'e1': ' 20% to 40% of men who undergo radical prostatectomy ', 'e2': 'biochemical recurrence ', 'relation': 'will develop ', 'condition': 'within 10 years after treatment'}, {'e1': 'and 30% to 50% of men who undergo radiation therapy ', 'e2': 'biochemical recurrence ', 'relation': 'will develop ', 'condition': 'within 10 years after treatment'}]"
223,P169P9,Radiomic features from pretreatment biparametric MRI can be predictive of prostate cancer biochemical recurrence after therapy and may help identify men who would benefit from adjuvant therapy.,"[{'e1': 'Radiomic features from pretreatment biparametric MRI ', 'e2': 'prostate cancer biochemical recurrence ', 'relation': 'can be predictive of ', 'condition': 'after therapy'}]"
224,P16P2,"Numerous long noncoding RNAs (lncRNAs) have recently emerged as targets for clinical translation. We previously identified 121 novel, differentially expressed prostate cancer (PCa) lncRNAs, including SChLAP1, which is overexpressed in a subset of tumors and associated with more aggressive disease. We subsequently validated a novel RNA in situ hybridization (ISH) assay for detection of SChLAP1 in formalin-fixed, paraffin-embedded (FFPE) tissue and used this assay to demonstrate that high SChLAP1 expression independently predicts biochemical PCa recurrence (ie, prostate-specific antigen [PSA] relapse) after radical prostatectomy in patients with clinically localized PCa. Although biochemical recurrence almost universally precedes clinical disease recurrence, many PCa patients with biochemical recurrence do not develop lethal disease. Given the predictive value of SChLAP1 ISH for biochemical recurrence after radical prostatectomy, we sought to investigate whether high SChLAP1 expression on ISH is also associated with development of lethal PCa (PCa-specific mortality or distant metastases).","[{'e1': 'Numerous long noncoding RNAs (lncRNAs) ', 'e2': ' targets', 'relation': 'have recently emerged as', 'condition': ' for clinical translation'}, {'e1': 'a novel RNA in situ hybridization (ISH) assay ', 'e2': 'SChLAP1 ', 'relation': 'for detection of ', 'condition': 'in formalin-fixed, paraffin-embedded (FFPE) '}, {'e1': 'high SChLAP1 expression ', 'e2': 'biochemical PCa recurrence ', 'relation': 'independently predicts ', 'condition': 'after radical prostatectomy in patients with clinically localized PCa'}, {'e1': 'high SChLAP1 expression ', 'e2': 'biochemical PCa recurrence after radical prostatectomy', 'relation': 'independently predicts ', 'condition': ' in patients with clinically localized PCa'}]"
225,P16P3,"In summary, high SChLAP1 expression on ISH independently predicts lethal PCa in a large cohort of American men with PCa during long-term follow-up, suggesting that SChLAP1 ISH is a promising biomarker for identifying patients at higher risk of lethal PCa progression.","[{'e1': 'high SChLAP1 expression on ISH ', 'e2': 'lethal PCa ', 'relation': 'independently predicts ', 'condition': 'in a large cohort of American men with PCa during long-term follow-up'}, {'e1': 'SChLAP1 ISH ', 'e2': 'patients ', 'relation': 'is a promising biomarker for identifying ', 'condition': 'at higher risk of lethal PCa progression.'}]"
226,P170P1,"MiR-1 and miR-143 are frequently reduced in human prostate cancer, while miR-141 and miR-21 are frequently elevated. Consequently, these miRNAs have been studied as cell-autonomous tumor suppressors and oncogenes. However, the cell-type specificity of these miRNAs is not well defined in prostate tissue. Through two different microdissection techniques, and droplet digital RT-PCR, we quantified these miRNAs in the stroma and epithelium of radical prostatectomy specimens. In contrast to their purported roles as cell-autonomous tumor suppressors, we found miR-1 and miR-143 expression to be predominantly stromal. Conversely, miR-141 was predominantly epithelial. miR-21 was detected in both stroma and epithelium. Strikingly, the levels of miR-1 and miR-143 were significantly reduced in tumor-associated stroma, but not tumor epithelium. Gene expression analyses in human cell lines, tissues, and prostate-derived stromal cultures support the cell-type selective expression of miR-1, miR-141, and miR-143. Analyses of the PCa Genome Atlas showed a strong positive correlation between stromal markers and miR-1 and miR-143, and a strong negative correlation between stromal markers and miR-141. In these tumors, loss of miR-1 and gain of miR-21 was highly associated with biochemical recurrence. These data shed new light on stromal and epithelial miRNA expression in the PCa tumor microenvironment.","[{'e1': ' loss of miR-1 and gain of miR-21 ', 'e2': 'biochemical recurrence', 'relation': 'was highly associated with ', 'condition': ' In these tumors'}]"
227,P171P1,"The TP53-MDM2-AR-AKT signalling network plays a critical role in the development and progression of prostate cancer. However, the molecular mechanisms regulating this signalling network are not fully defined. By conducting transcriptome analysis, denaturing immunoprecipitations and immunopathology, we demonstrate that the TP53-MDM2-AR-AKT cross-talk is regulated by the deubiquitinating enzyme USP12 in prostate cancer. Our findings explain why USP12 is one of twelve most commonly overexpressed cancer-associated genes located near an amplified super-enhancer. We find that USP12 deubiquitinates MDM2 and AR which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer. Consequently, USP12 levels are predictive not only of cancer development but also of patient’s therapy resistance, relapse and survival. Therefore, our findings suggest that USP12 could serve as a promising therapeutic target in currently incurable castrate resistant prostate cancer.","[{'e1': ' the TP53-MDM2-AR-AKT cross-talk', 'e2': 'the deubiquitinating enzyme USP12', 'relation': ' is regulated by ', 'condition': ' in prostate cancer'}]"
228,P171P2,"TP53, the guardian of the genome, is a potent transcriptional regulator and a crucial tumour suppressor. Following ubiquitination by MDM2, TP53 is targeted for proteosomal degradation resulting in increased proliferation and tumourigenesis. The ubiquitination event occurs within the nucleus. MDM2 can also directly ubiquitinate the androgen receptor leading to its degradation. AR is a transcription factor critical in prostate cancer development and progression, with increased AR activity promoting prostate cell proliferation and survival. Consequently, by targeting both TP53 and AR proteins, MDM2 acts to control the balance between pro- and anti-proliferative pathways in prostate cancer.","[{'e1': ' MDM2 ', 'e2': ' pro- and anti-proliferative pathways ', 'relation': 'acts to control the balance between', 'condition': 'in prostate cancer.'}]"
229,P171P3,"We have previously reported that AR can be directly deubiquitinated and stabilised by ubiquitin specific peptidase 12. USP12, when bound to its cofactors UAF1 and WDR20, can also deubiquitinate the AKT phosphatases PHLPP and PHLPPL. This activity controls the AR-AKT signalling network in which AKT can phosphorylate the AR at serines 213 and 791 which, in turn, targets it for ubiquitination by MDM2 and subsequent proteosomal degradation. Additionally, AKT can also phosphorylate MDM2 at serines 166 and 188 which promotes MDM2 nuclear translocation and inhibits its auto-ubiquitination and proteosomal degradation. Aberrant activity of AKT signalling is one of the most common features of the aggressive castrate resistant prostate cancer.","[{'e1': 'USP12 ', 'e2': ' the AKT phosphatases PHLPP and PHLPPL', 'relation': 'can deubiquitinate', 'condition': 'when bound to its cofactors UAF1 and WDR20'}]"
230,P172P3,"Increases in androgen deprivation therapy Response Signature score were associated with a reduction in risk of metastasis only in adjuvant androgen deprivation therapy patients. On multivariable analysis, androgen deprivation therapy Response Signature by androgen deprivation therapy treatment interaction term remained associated with metastasis in both validation sets. In a matched validation set, patients with low androgen deprivation therapy Response Signature scores had similar 10-year metastasis rates in the adjuvant androgen deprivation therapy and no androgen deprivation therapy groups. Among high androgen deprivation therapy Response Signature patients, 10-year metastasis rates were significantly lower for adjuvant androgen deprivation therapy versus no androgen deprivation therapy patients. The marginal androgen deprivation therapy Response Signature by androgen deprivation therapy interaction remained significant in the matched dataset.","[{'e1': 'Increases in androgen deprivation therapy Response Signature score ', 'e2': 'a reduction in risk of metastasis ', 'relation': 'were associated with ', 'condition': 'only in adjuvant androgen deprivation therapy patients'}, {'e1': ' androgen deprivation therapy Response Signature by androgen deprivation therapy treatment interaction term ', 'e2': ' metastasis in both validation sets', 'relation': 'remained associated with', 'condition': ' In multivariable analysis'}]"
231,P172P4,"Patients with high androgen deprivation therapy Response Signature benefited from adjuvant androgen deprivation therapy. In combination with prognostic risk factors, use of androgen deprivation therapy Response Signature may thus allow for identification of androgen deprivation therapy-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early androgen deprivation therapy after surgery.","[{'e1': 'a gene signature that when present in primary prostate tumors ', 'e2': 'patients who may respond to early androgen deprivation therapy ', 'relation': 'may be useful to predict ', 'condition': 'after surgery.'}]"
232,P172P5,"Androgen deprivation therapy has served as the foundation for advanced prostate cancer management since its discovery by Huggins and Hodges in 1941. In fact, in the United States, approximately half of all prostate cancer patients will receive a course of androgen deprivation therapy at some point during treatment. In the primary radiotherapy setting, a large body of evidence supports the radiosensitizing properties of adjuvant androgen deprivation therapy and a resultant overall survival benefit. Similarly, in men with lymph node-positive disease after radical prostatectomy, adjuvant androgen deprivation therapy has demonstrated a survival benefit. Furthermore, large retrospective series have also suggested improved cancer specific mortality with adjuvant androgen deprivation therapy in the presence of seminal vesicle invasion on surgical pathology. Indeed, the adjuvant androgen deprivation therapy arm of the SWOG S9921 trial of high-risk prostate cancer treated with radical prostatectomy demonstrated a 92% 5-year biochemical recurrence-free survival. Furthermore, several institutions have published favorable results with adjuvant androgen deprivation therapy after radical prostatectomy for high-risk prostate cancer. In fact, an analysis of SEER-Medicare data found that 23% of high-risk prostate cancer patients undergoing radical prostatectomy received adjuvant androgen deprivation therapy. Thus, while the majority of radical prostatectomy patients do not receive adjuvant androgen deprivation therapy, there are a significant number of high-risk prostate cancer patients receiving adjuvant androgen deprivation therapy in the United States after radical prostatectomy.","[{'e1': ' adjuvant androgen deprivation therapy ', 'e2': ' a survival benefit', 'relation': 'has demonstrated', 'condition': ' in men with lymph node-positive disease after radical prostatectomy'}, {'e1': ' large retrospective series', 'e2': ' improved cancer specific mortality with adjuvant androgen deprivation therapy ', 'relation': ' have also suggested', 'condition': 'in the presence of seminal vesicle invasion on surgical pathology'}, {'e1': ' a large body of evidence ', 'e2': 'the radiosensitizing properties of adjuvant androgen deprivation therapy and a resultant overall survival benefit', 'relation': 'supports ', 'condition': ' In the primary radiotherapy setting'}]"
233,P173P1,"Recurrence of high-grade prostate cancer after radiotherapy is a significant clinical problem, resulting in increased morbidity and reduced patient survival. The molecular mechanisms of radiation resistance are being elucidated through the study of microRNA that negatively regulate gene expression. We performed bioinformatics analyses of The Cancer Genome Atlas dataset to evaluate the association between miR-106a and its putative target lipopolysaccharide-induced TNF-a factor in prostate cancer. We characterized the function of miR-106a through in vitro and in vivo experiments and employed transcriptomic analysis, western blotting, and 3′ UTR luciferase assays to establish LITAF as a bona fide target of miR-106a. Using our well-characterized radiation-resistant cell lines, we identified that miR-106a was overexpressed in radiation-resistant cells compared to parental cells. In the TCGA, miR-106a was significantly elevated in high-grade human prostate tumors relative to intermediate- and low-grade specimens. An inverse correlation was seen with its target, LITAF. Furthermore, high miR-106a and low LITAF expression predict for biochemical recurrence at 5 years after radical prostatectomy. miR-106a overexpression conferred radioresistance by increasing proliferation and reducing senescence, and this was phenocopied by knockdown of LITAF. For the first time, we describe a role for miRNA in upregulating ATM expression. LITAF, not previously attributed to radiation response, mediates this interaction. This route of cancer radioresistance can be overcome using the specific ATM kinase inhibitor, KU-55933. Our research provides the first report of miR-106a and LITAF in prostate cancer radiation resistance and high-grade disease, and presents a viable therapeutic strategy that may ultimately improve patient outcomes.","[{'e1': ' high miR-106a and low LITAF expression ', 'e2': ' biochemical recurrence ', 'relation': 'predict for', 'condition': 'at 5 years after radical prostatectomy'}, {'e1': 'miR-106a overexpression ', 'e2': 'radioresistance ', 'relation': 'conferred ', 'condition': 'by increasing proliferation and reducing senescence'}]"
234,P173P3,"MicroRNA are small noncoding RNA that negatively regulate gene expression. miRNA are transcribed into long stem loop structures that ultimately form a double-stranded RNA. The dominant RNA strand is incorporated into the RNA silencing complex to facilitate target mRNA binding, and the complementary strand is degraded. miRNA decrease protein expression of their target mRNA by binding imperfectly to nucleotides in the seed sequence in the mRNA 3′ untranslated region. Transcript degradation is the major outcome of miRNA-mRNA binding, occurring through the 5′-to-3′ mRNA decay pathway.","[{'e1': 'miRNA ', 'e2': 'protein expression of their target mRNA', 'relation': 'decrease ', 'condition': ' by binding imperfectly to nucleotides in the seed sequence in the mRNA 3′ untranslated region'}]"
235,P173P5,"We identified miR-106a from a next-generation sequencing screen of radiation-resistant PC3 cells. Bioinformatics analyses of The Cancer Genome Atlas dataset revealed that miR-106a was significantly higher in prostate tumors compared to normal prostate. miR-106a showed significantly higher expression in high-grade prostate tumors compared to low- and intermediate-grade tumors, suggesting that miR-106a may be involved in disease progression. We discovered that miR-106a increased survival and growth after ionizing radiation using in vitro and in vivo prostate cancer models. We also confirmed that miR-106a targets lipopolysaccharide-induced TNF-a factor to produce this radioresistant phenotype. In addition, we found that high miR-106a and low LITAF expression predict for decreased biochemical recurrence-free survival at 5 years after radical prostatectomy. In this study, we describe for the first time two novel players in prostate cancer radioresistance: miR-106a and LITAF. We describe a novel mechanism where miR-106a overexpression and LITAF knockdown upregulate ATM expression. Inhibition of ATM kinase activity with KU-55933 resensitized miR-106a-overexpressing cells to radiation, highlighting a promising therapeutic intervention for miR-106a radioresistant prostate cancer.","[{'e1': 'miR-106a ', 'e2': 'survival and growth ', 'relation': 'increased ', 'condition': 'after ionizing radiation using in vitro and in vivo prostate cancer models'}, {'e1': 'high miR-106a and low LITAF expression ', 'e2': 'decreased biochemical recurrence-free survival', 'relation': 'predict for ', 'condition': ' at 5 years after radical prostatectomy'}]"
236,P173P6,"This study has identified a new miRNA involved in prostate cancer radiotherapy resistance. miR-106a is significantly upregulated in human prostate tumors, with increased expression in high-grade tumors compared to low- and intermediate-grade tumors. We also show for the first time a novel role for LITAF in regulating radioresistance, where knockdown of LITAF induces increased survival and proliferation after radiation. LITAF expression shows the opposite trend as miR-106a in the TCGA dataset, and in addition, the combination of high miR-106a and low LITAF expression predicts for biochemical recurrence at 5 years after radical prostatectomy. We propose a model whereby miR-106a targets LITAF, resulting in ATM upregulation and radioresistance. This may be independent of ATM’s role in DNA damage repair. In addition, we have identified KU-55933 as a potential therapeutic intervention in combination with radiation, to radiosensitize miR-106a-induced radiation-resistant prostate cancer. Our findings identify miR-106a and LITAF as novel modulators of radioresistance through ATM upregulation and suggest that miR-106a may be a promising biomarker for high-grade disease and radioresistant prostate cancer.","[{'e1': ' the combination of high miR-106a and low LITAF expression ', 'e2': 'biochemical recurrence ', 'relation': 'predicts for ', 'condition': 'at 5 years after radical prostatectomy'}, {'e1': 'knockdown of LITAF', 'e2': 'increased survival and proliferation ', 'relation': ' induces ', 'condition': 'after radiation'}]"
237,P174P9,"Active surveillance rather than immediate treatment is now widely endorsed as a preferred management strategy for low-risk prostate cancer and is offered to a growing proportion of men both in the USA and internationally. An important goal of contemporary investigation into the biology of low-risk prostate cancer is to help determine which of the low-grade prostate cancers are highly aggressive and merit immediate treatment, need close active surveillance, and could be safely followed with a less active monitoring strategy. We aimed to characterize the genomic expression patterns of tumors with relatively homogeneous, low-risk clinical characteristics, to determine whether such tumors are characterized by similarly homogeneous expression patterns, both in terms of genomically determined clinical risk and in terms of tumor subtyping based on broader expression analysis.","[{'e1': 'Active surveillance rather than immediate treatment ', 'e2': 'a preferred management strategy ', 'relation': 'is now widely endorsed as ', 'condition': 'for low-risk prostate cancer'}]"
238,P175P3,"PSCA staining was absent in normal epithelial and stromal cells of the prostate. Membranous and cytoplasmic PSCA staining was seen in 53.7% of 9642 interpretable tumors. Staining was weak in 22.4%, moderate in 24.5% and strong in 6.8% of tumors. PSCA expression was associated with favorable pathological and clinical tumor features: early pathological tumor stage, low Gleason grade, absence of lymph node metastasis, low pre-operative PSA level, negative surgical margin and reduced PSA recurrence. PSCA expression was an independent predictor of prognosis in multivariate analysis (hazard ratio 0.84, p < 0.0001).","[{'e1': 'PSCA expression ', 'e2': 'prognosis ', 'relation': 'was an independent predictor of ', 'condition': 'in multivariate analysis '}]"
239,P175P6,"Prostate stem cell antigen (PSCA) is a protein of unknown function anchored to the cell surface. It was discovered in an attempt to identify genes up regulated in human prostate cancer. Though the name implies specificity for the prostate, PSCA is expressed in several tissues: placenta, kidney, pancreas, and bladder. The function of PSCA has not been fully elucidated. Experiments suggest a possible role in cell adhesion, proliferation control and cell survival. Evidence is accumulating that, depending on the cell type involved, PSCA can have a tumor promoting or a tumor suppressive effect. For example, loss of PSCA was associated with poor outcome in cancer of the gallbladder and stomach, but with improved prognosis in pancreatic adenocarcinoma, renal cell carcinoma and non-small lung cancer. The part of PSCA in prostate cancer remains unclear. Even if most available data suggest that prostate cancer may belong to the tumors with an oncogenic function of PSCA overexpression, there are also studies that do not support such a conclusion or suggest the opposite that prostate cancer aggressiveness and metastasis is driven by PSCA down regulation.","[{'e1': 'loss of PSCA ', 'e2': 'poor outcome ', 'relation': 'was associated with ', 'condition': 'in cancer of the gallbladder and stomach'}]"
240,P177P6,"Regarding IFN-γ, prostate cancer cells have been shown to be poorly sensitive to its cytotoxic effects. Furthermore, it has been suggested that IFN-γ might induce immune-suppressive effects in prostate cancer.","[{'e1': 'IFN-γ ', 'e2': 'immune-suppressive effects ', 'relation': 'might induce ', 'condition': 'in prostate cancer.'}]"
241,P177P7,"In this study, we have comparatively analyzed the expression of genes encoding IFN-γ, TNF-α, and their receptors in prostate cancer and in benign prostatic hyperplasia tissues. Moreover, we have investigated the ability of these cytokines to induce in prostate cancer cells the production of factors promoting tumor progression through the inhibition of adaptive immune responses and or the activation of alternative pathways for the androgen receptor. Finally, we have addressed the prognostic significance of factors induced by IFN-γ and TNF-α in prostate cancer cells and their potential predictive power when detected in urine of individuals at risk of developing this malignancy.","[{'e1': ' cytokines ', 'e2': 'the production of factors promoting tumor progression ', 'relation': 'induce ', 'condition': 'in prostate cancer cells'}, {'e1': 'production of factors ', 'e2': 'tumor progression ', 'relation': 'promoting ', 'condition': 'through the inhibition of adaptive immune responses '}, {'e1': 'production of factors ', 'e2': 'tumor progression ', 'relation': 'promoting ', 'condition': 'through activation of alternative pathways for the androgen receptor'}]"
242,P177P8,"A major problem in prostate cancer treatment is represented by the individuation of patients requiring more aggressive therapeutic approaches, while avoiding overtreatment of the others. Therefore, the characterization of predictive prostate cancer markers is of paramount clinical importance. Within this context, our results identify IDO as a predictor of poor prognosis in prostate cancer, and the corresponding protein as a potential therapeutic target.","[{'e1': 'IDO', 'e2': 'poor prognosis ', 'relation': ' is a predictor of ', 'condition': 'in prostate cancer'}]"
243,P178P2,"Comprehensive genomic analyses have substantially furthered our understanding of primary prostate cancer and metastatic castration-resistant prostate cancer. These studies have discovered common genetic drivers of prostate cancer, such as fusions of ETS genes, amplification of AR, and loss of CDKN2A, PTEN, RB1, SPOP, and TP53. Integrative genomic studies have further delineated distinct molecular subtypes in primary and metastatic prostate cancer and specific molecular pathways that contribute to prostate cancer onset and progression, including AR, WNT, and PI3K/AKT/MTOR signaling.","[{'e1': 'Integrative genomic studies ', 'e2': 'distinct molecular subtypes ', 'relation': 'have further delineated ', 'condition': 'in primary and metastatic prostate cancer '}]"
244,P178P4,"CDK12 is a cyclin-dependent kinase that associates with its activating partner, cyclin K, to form a heterodimeric complex that regulates several critical cellular processes. CDK12 consists of different functional domains: a centrally located kinase domain, several RS motifs near the N-terminus, and a proline-rich motif which can function as a binding site for additional proteins. CDK12 directly regulates transcription by phosphorylating serine residues of the hepta-peptide repeats within the C-terminal domain of RNA polymerase II essential for transcriptional elongation. Multiple studies have also suggested a role for CDK12 in controlling genomic stability through regulation of genes involved in the DNA damage response. Depletion or loss of function of CDK12 have further been observed to sensitize ovarian cancer cells to poly ADP ribose polymerase inhibitors through defects in homologous recombination.","[{'e1': ' CDK12 ', 'e2': 'transcription ', 'relation': 'directly regulates ', 'condition': 'by phosphorylating serine residues of the hepta-peptide repeats within the C-terminal domain of RNA polymerase II essential for transcriptional elongation'}, {'e1': ' CDK12 ', 'e2': 'genomic stability ', 'relation': ' controls ', 'condition': 'through regulation of genes involved in the DNA damage response'}, {'e1': 'Depletion or loss of function of CDK12 ', 'e2': 'ovarian cancer cells to poly ADP ribose polymerase inhibitors ', 'relation': 'have further been observed to sensitize ', 'condition': 'through defects in homologous recombination.'}]"
245,P179P1,"Nuclear alterations are a hallmark of many types of cancers, including prostate cancer. Recent evidence shows that subvisual changes, ones that may not be visually perceptible to a pathologist, to the nucleus and its ultrastructural components can precede visual histopathological recognition of cancer. Alterations to nuclear features such as nuclear size and shape, texture, and spatial architecture reflect the complex molecular-level changes that occur during oncogenesis. Quantitative nuclear morphometry, a field that uses computational approaches to identify and quantify malignancy-induced nuclear changes, can enable a detailed and objective analysis of the prostate cancer cell nucleus. Recent advances in machine learning-based approaches can now automatically mine data related to these changes to aid in diagnostic decision-making and prediction of prostate cancer prognoses. In this review, we use prostate cancer as a case study to connect the molecular-level mechanisms that underlie these nuclear changes to the machine learning computational approaches, bridging the gap between the clinical and computational understanding of prostate cancer. First, we discuss recent developments to our understanding of molecular events that drive nuclear alterations in the context of prostate cancer: the role of the nuclear matrix and lamina in size and shape changes, the role of three-dimensional chromatin organization and epigenetic modifications in textural changes, and the role of the tumor microenvironment in altering nuclear spatial topology. We then discuss the advances in the applications of machine learning algorithms to automatically segment nuclei in prostate histopathological images, extract nuclear features to aid in diagnostic decision-making, and predict potential outcomes such as biochemical recurrence and survival. Lastly, we discuss the challenges and opportunities associated with translation of the quantitative nuclear morphometry methodology into the clinical space. Ultimately, accurate identification and quantification of nuclear alterations can contribute to the field of nucleomics and has applications for computationally driven precision oncologic patient care.","[{'e1': ' Alterations to nuclear features', 'e2': 'the complex molecular-level changes that occur ', 'relation': 'reflect ', 'condition': 'during oncogenesis'}]"
246,P179P2,"Prior to the widespread utilization of prostate-specific antigen in the late 1980s, over 50% of patients who presented with prostate cancer exhibited advanced disease. Now, however, use of the prostate-specific antigen test has resulted in overdiagnosis and the overtreatment of many indolent tumors that would not have caused harm during a patient’s lifetime. In addition, despite early interventions, nearly 20%–40% of patients still experience cancer recurrence following radical prostatectomy.","[{'e1': ' over 50% of patients who presented with prostate cancer ', 'e2': 'advanced disease', 'relation': 'exhibited ', 'condition': 'Prior to the widespread utilization of prostate-specific antigen in the late 1980s'}, {'e1': 'nearly 20%–40% of patients ', 'e2': 'cancer recurrence ', 'relation': 'still experience ', 'condition': 'following radical prostatectomy.'}]"
247,P179P3,"Prostate cancer biology can be characterized largely by genetic instability. While hereditary cancers only account for a minority of prostate cancer, the majority of cases emerge from somatic mutations. It is believed that the late onset of prostate cancer suggests that genetic changes leading to oncogenesis accumulate over many years before clinical presentation. Studies indicate that chronic infections, inflammation, and numerous genotoxic insults can initiate genetic instability and lead to cancer formation through both genetic and epigenetic changes. Further, prostate cancer is also considered to be a highly heterogeneous disease, which is reflected in the fact that multiple histologic patterns of cancer can be found within the same gland during Gleason scoring by expert pathologists. As such, due to the complexity and multitude of gene alterations that have been shown to drive prostate cancer progression, finding a unifying genetic signature and identifying specific subtypes of prostate cancer has proved elusive to date.","[{'e1': 'chronic infections, inflammation, and numerous genotoxic insults ', 'e2': 'cancer formation ', 'relation': 'lead to ', 'condition': 'through both genetic and epigenetic changes'}]"
248,P179P4,"Transformation of normal prostate epithelium due to accumulated genetic and epigenetic changes can be phenotypically identified by observation of alterations to both the nuclear and tissue architecture. It has long been noted that disruptions to the organization of normal nuclear architecture are a hallmark of cancer. While defects in nuclear structure and function themselves do not cause cancer development, the altered nuclear organization in cancer cells is a manifestation of transformative and progressive oncogenic events. Malignancy-induced nuclear changes may have profound implications for three-dimensional chromatin organization and folding, the fidelity of genome replication, and the regulatory mechanisms of gene expression. Despite the many pleiotropic and pleiomorphic variations studied in the cancer cell nucleus, the underlying mechanisms that cause these changes and the functional links that lead to malignancy are poorly understood to date. Yet, changes to nuclear architecture, including nuclear enlargement and prominent nucleoli, are key features used by pathologists to identify cancerous regions from benign regions across many cancer types. Recent efforts to quantify these changes to cancer cell nuclei using computer-aided methods for use in the diagnostic, prognostic, and therapeutic spheres have been substantial. Quantitative nuclear morphometry, a field that uses computational approaches to identify and quantify malignancy-induced nuclear changes, has emerged as a potential solution to meet the clinical needs of early identification of prostate cancer at the cellular and molecular level. Semi-automated methods developed in the early 2000s showed initial benefits in the diagnostic space but required manual identification of cancer nuclei. Previous limitations in efficiency and reproducibility have now sparked a revolution of new, fully automated algorithms that utilize machine learning to segment nuclei, extract and quantify nuclear features, and use these features to predict prostate cancer progression. While several companion diagnostic genomic and proteomic assays are commercially available, they fail to capture the full extent of disease heterogeneity as they only sample a small part of the tumor landscape. On the contrary, computer-assisted approaches are able to identify subvisual nuclear changes in histological images that are unavailable to the human eye and not captured in genomic and proteomic analyses, and they allow for a larger coverage of the tumor landscape in both cancerous and benign-adjacent regions. Machine learning methods are able to uniquely discover patterns and relationships within and between cancer cell nuclei from complex datasets to effectively predict future outcomes. This digital transformation in oncology and pathology has the potential to provide new tools to aid clinicians in decision-making for more precision-based approaches.","[{'e1': ' computer-assisted approaches ', 'e2': 'subvisual nuclear changes ', 'relation': 'are able to identify ', 'condition': 'in histological images that are unavailable to the human eye and not captured in genomic and proteomic analyses'}, {'e1': ' computer-assisted approaches ', 'e2': 'a larger coverage of the tumor landscape ', 'relation': ' allow for ', 'condition': 'in both cancerous and benign-adjacent regions'}]"
249,P17P10,"Tremendous enthusiasm has developed for the use of circulating tumor cells for real-time monitoring of dynamic events in both primary and metastatic cancer settings without the need for invasive tissue biopsy. A great deal has been learned through the analysis of circulating tumor content regarding the prevalence and clonality of common prostate cancer deletions and mutations in cases with multiple metastatic foci, the enhanced expression of EMT-related genes in CRPC patients, AR mutation and amplification status and sustained AR signaling in the presence of hormone therapy. Our analysis showed that Panel A and B expression values were similar across recurrent prostate cancer patients regardless of whether or not they have developed resistance to antiandrogen therapy, thus they may have limited value beyond their strong performance in the primary cancer setting for predicting recurrence. Some controversy exists relating to the number of CTCs that can be isolated from primary versus metastatic prostate cancer patients, but future efforts should be made to determine whether CTC gene expression analysis could be applied to primary prostate cancer patients for the prediction of subsequent recurrence.","[{'e1': 'Tremendous enthusiasm ', 'e2': 'circulating tumor cells for real-time monitoring of dynamic events ', 'relation': 'has developed for the use of ', 'condition': 'in both primary and metastatic cancer settings without the need for invasive tissue biopsy'}, {'e1': ' the analysis of circulating tumor content ', 'e2': 'prevalence and clonality of common prostate cancer deletions and mutations ', 'relation': 'regarding the ', 'condition': 'in cases with multiple metastatic foci'}, {'e1': 'Panel A and B expression values ', 'e2': 'strong performance ', 'relation': 'may have limited value beyond their ', 'condition': 'in the primary cancer setting for predicting recurrence'}]"
250,P17P11,"Finally, our findings collectively suggest that pCREB1 alone may not be an all-inclusive indicator of aggressive prostate cancer. While the phosphorylation of CREB1 is a partial marker of CREB1 transcriptional activity with demonstrated utility in identifying aggressive disease, it does not account for the phosphorylation-independent mechanisms of transactivation, which we now see can be potentiated by the cooperative function of FoxA1 and by the co-regulatory role of MED1. Thus, measuring total CREB1 transcriptional output, or that of a representative subset of disease-relevant genes, will likely afford increased sensitivity in predicting outcomes over pCREB1 levels alone.","[{'e1': 'the phosphorylation of CREB1 ', 'e2': 'CREB1 transcriptional activity with demonstrated utility ', 'relation': 'is a partial marker of ', 'condition': 'in identifying aggressive disease'}]"
251,P17P2,"The complexity, heterogeneity and plasticity of prostate cancer have proven major obstacles in our understanding of the etiology and progression of this disease and have provided a rich source for discovery of novel cancer concepts and a platform for the development of new analytical methods. Critical questions remain as to the optimal approaches to characterize aggressive versus indolent disease in the clinically localized setting, the factors that predict treatment response and failure, and the mechanisms underlying therapeutic failure that reveal novel targets for effective intervention. Specifically, the discovery of targetable prostate cancer drivers outside the androgen/androgen receptor (AR) signaling axis is paramount to achieving cures and improving the duration of therapeutic response. The importance of this concept is made increasingly apparent by the mounting reports of resistance to even the most potent second-generation antiandrogen therapeutics and continually emerging molecular mechanisms underlying such treatment failure.","[{'e1': 'Critical questions remain as to the optimal approaches', 'e2': 'aggressive versus indolent disease ', 'relation': ' to characterize ', 'condition': 'in the clinically localized setting'}]"
252,P17P3,"Genomic analyses of primary and advanced metastatic prostate cancers have endeavored to reveal the alterations characterizing aggressive disease in hopes of identifying novel driver genes and pathways. While potentially clinically actionable mutations in PI3K (PIK3CB), RAF, DNA repair (ATM and BRCA1/2) and cell cycle (CDK4) pathways were discovered in metastatic CRPC patient samples, primary cancer studies have returned few therapeutic candidates beyond AR itself. Additionally, while genome-wide copy number alteration (CNA) alone or in combination with additional tumor characteristics provide valuable prognostic information for effective risk stratification to aid in early clinical decision making, they do not immediately identify the therapeutic compounds from which a high-risk prostate cancer patient may benefit. These observations encourage an alternate, mechanistic approach to the discovery of targetable disease-driving pathways that can simultaneously predict risk and indicate potential therapeutic strategies early in the course of treatment.","[{'e1': 'potentially clinically actionable mutations ', 'e2': 'in PI3K (PIK3CB), RAF, DNA repair (ATM and BRCA1/2) and cell cycle (CDK4) pathways ', 'relation': 'were discovered ', 'condition': 'in metastatic CRPC patient samples'}]"
253,P17P4,"Our recent analysis of the pioneer transcription factor FoxA1 revealed its collaborative relationship with the cAMP response element binding protein (CREB1) in determining the expression of G1/S phase cell cycle progression genes. Additionally, these factors support the androgen-independent AR-mediated expression of G2/M phase cell cycle enhancers in CRPC cells. These results suggest that comprehensive analysis of genome-wide CREB1/FoxA1 cooperativity may define disease-relevant gene expression profiles during the evolution and progression of human prostate cancer.","[{'e1': 'androgen-independent AR-mediated', 'e2': ' G2/M phase cell cycle enhancers ', 'relation': ' expression of', 'condition': 'in CRPC cells.'}]"
254,P17P5,"Individually, while FoxA1 has been well characterized, CREB1-mediated transcription remains largely unexplored in prostate cancer. This important second messenger-responsive transcription factor (TF), in addition to promoting cell cycle progression, has been implicated in several prostate cancer-relevant functions including steroidogenesis and bone metastasis . CREB1 is also emerging as a key mediator of metabolic programs in cancer cells, orchestrating the response to metabolic stress and multiple extracellular hormonal signals. Its kinase-inducible transactivation, minimally by Serine 133 phosphorylation resulting in CREB binding protein (CBP)/p300 recruitment to target gene loci, can be stimulated by multiple signaling pathways, some of which are deregulated in prostate cancer (ex. IGF-I and PI3K/Akt). Consequently, CREB1 signaling represents an attractive therapeutic candidate. Complete profiling of CREB1 target genes should therefore expand on these insights and provide a rationale for the development and use of direct or indirect CREB1-inhibiting compounds in prostate cancer prevention or therapy.","[{'e1': 'CREB1 ', 'e2': 'metabolic programs ', 'relation': 'is also emerging as a key mediator of ', 'condition': 'in cancer cells'}]"
255,P17P6,"Utilizing the LNCaP and abl cell lines, which model hormone-dependent and -independent growth characteristics as well as the clinical properties of a significant portion of ADPC (androgen-dependent prostate cancer) and CRPC (castration-resistant prostate cancer) patients, respectively, the current study is the first to explore genome-wide CREB1 signaling individually and in collaboration with FoxA1. Our integrated genomics approach compiles CREB1 and FoxA1 binding site data with gene expression profiles of transcripts responsive to individual TF silencing to characterize cooperative CREB1/FoxA1 transcriptional activity. We also utilize these genomic datasets in a knowledge-driven approach to the discovery of prognostic gene panels. We have demonstrated that coordinated CREB1/FoxA1 signaling contributes to disease-relevant transcription programs in both ADPC and CRPC cells. We further show that CRPC-associated CREB1/FoxA1 target genes provide valuable tools for assessing risk of prostate cancer recurrence in primary patient tissues. Importantly, we demonstrate that CREB1/FoxA1 transcriptional activity is sensitive to kinase inhibitors that impact the transcription co-regulator MED1. We propose that this work reveals a potentially targetable transcription regulatory signaling axis that may serve as a robust biomarker of disease recurrence.","[{'e1': 'We also utilize these genomic datasets ', 'e2': 'prognostic gene panels', 'relation': 'to the discovery of ', 'condition': ' in a knowledge-driven approach'}, {'e1': 'coordinated CREB1/FoxA1 signaling ', 'e2': 'disease-relevant transcription programs ', 'relation': 'contributes to ', 'condition': 'in ADPC cells '}, {'e1': 'coordinated CREB1/FoxA1 signaling ', 'e2': 'in CRPC cells', 'relation': 'contributes to ', 'condition': 'in CRPC cells'}, {'e1': 'CRPC-associated CREB1/FoxA1 target genes', 'e2': 'prostate cancer recurrence', 'relation': ' provide valuable tools for assessing risk of ', 'condition': ' in primary patient tissues'}]"
256,P181P2,"Multi-omics molecular profiling was carried out on post-radical prostatectomy material from a cohort of 130 patients with localized prostate cancer. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas cohort were used to characterize the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned.","[{'e1': 'Multi-omics molecular profiling ', 'e2': 'post-radical prostatectomy material ', 'relation': 'was carried out on ', 'condition': 'from a cohort of 130 patients with localized prostate cancer'}]"
257,P181P5,"Prostate cancer is the most frequent cancer diagnosed in men, accounting for 15% of all male cancer cases diagnosed. Regardless of this incidence, the associated death rate remains relatively low since 10% of men diagnosed with prostate cancer will die of their disease. According to randomized studies on localized prostate cancer management, 20% of cancers will progress to metastatic state and death after more than 10 years of follow-up. These studies suggest that a majority of cancers diagnosed at a localized stage are exposed to overtreatment.","[{'e1': ' 20% of cancers ', 'e2': ' metastatic state ', 'relation': 'will progress to', 'condition': 'after more than 10 years of follow-up'}, {'e1': ' 20% of cancers ', 'e2': 'death ', 'relation': 'will progress to', 'condition': 'after more than 10 years of follow-up'}]"
258,P182P1,"Prognostic biomarkers for localized prostate cancer could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers.","[{'e1': ' panel of differentially methylated CpGs ', 'e2': 'disease aggressiveness', 'relation': 'predicts ', 'condition': 'in primary tumor tissue '}]"
259,P182P6,"Molecular studies of tumor tissue have led to development of commercial tests based on gene expression scores for prediction of metastasis or prostate cancer death after prostatectomy, with AUC values ranging from 0.75 to 0.82 for these mRNA-based assays. However, rigorous comparative effectiveness studies of these assays and prospective clinical studies are needed to confirm the performance characteristics of these tests. In addition, there are other fluid-based and tumor tissue-based biomarker panels that may aid risk stratification of men diagnosed with localized disease, but these also require further evaluation.","[{'e1': 'Molecular studies of tumor tissue ', 'e2': 'development of commercial tests ', 'relation': 'have led to ', 'condition': 'based on gene expression scores for prediction of metastasis or prostate cancer death after prostatectomy'}]"
260,P182P9,"In summary, we have created and validated a tumor-tissue based DNA methylation score to predict metastatic progression and prostate cancer death in men diagnosed with clinically localized prostate cancer. Compared to Gleason sum alone, the score incorporating five CpGs and Gleason sum provided better prognostic stratification, with a 4.6% increase in AUC and a 48% increase in pAUC. The score increased sensitivity from 53% for Gleason sum alone to 74% for the score at 95% specificity, representing a 39.6% improvement in identification of truly high-risk men who may benefit from adjuvant therapy and more intense surveillance for metastatic progression following radical prostatectomy. In terms of clinical translation, at 100% specificity the DNA methylation score was able to identify six additional high-risk patients with metastatic-lethal events in the testing dataset who would have been missed based on the use of Gleason sum alone or Gleason sum, diagnostic PSA and pathologic stage combined for risk stratification. This indicates that with high specificity the methylation score could markedly improve the selection of patients at high risk for metastatic-lethal progression, which is particularly relevant for those patients who may be misclassified as low risk and forego potentially life-saving adjuvant treatment. Given these promising results, this prognostic tumor DNA methylation score warrants further evaluation for its clinical utility and ability to improve prostate cancer patient outcomes.","[{'e1': 'a tumor-tissue based DNA methylation score created ', 'e2': 'metastatic progression ', 'relation': 'to predict ', 'condition': 'in men diagnosed with clinically localized prostate cancer'}, {'e1': 'a tumor-tissue based DNA methylation score created ', 'e2': 'prostate cancer death ', 'relation': 'to predict ', 'condition': 'in men diagnosed with clinically localized prostate cancer'}]"
261,P183P3,"We identified a 4-miRNA ratio model, MiCaP, defined as (miR-23a-3p √ó miR-10b-5p) / (miR-133a √ó miR-374b-5p), that predicted time to biochemical recurrence independently of routine clinicopathologic variables in the training cohort and was successfully validated in two independent radical prostatectomy cohorts. In addition, MiCaP was a significant predictor of prostate cancer-specific survival in univariate analysis and in multivariate analysis. As proof-of-principle, we also analyzed MiCaP in plasma samples from 111 radical prostatectomy patients. A high MiCaP score in plasma was significantly associated with biochemical recurrence. Limitations include low mortality rates.","[{'e1': ' MiCaP ', 'e2': 'prostate cancer-specific survival ', 'relation': 'was a significant predictor of ', 'condition': 'in univariate analysis '}, {'e1': ' MiCaP ', 'e2': ' time to biochemical recurrence ', 'relation': 'predicted', 'condition': 'independently of routine clinicopathologic variables in the training cohort'}, {'e1': 'A high MiCaP score ', 'e2': 'biochemical recurrence.', 'relation': 'was significantly associated with ', 'condition': 'in plasma'}, {'e1': ' MiCaP ', 'e2': 'prostate cancer-specific survival ', 'relation': 'was a significant predictor of ', 'condition': 'in multivariate analysis'}]"
262,P183P5,"Prostate cancer is the most commonly diagnosed cancer in men in the Western world. Currently, serum prostate-specific antigen is used for detection of prostate cancer and for monitoring of disease progression and treatment response. Over the past decades, extensive use of prostate-specific antigen testing has increased detection rates for early stage tumors, which may be cured by radical prostatectomy. However, available prognostic indicators including prostate-specific antigen, tumor stage, and Gleason score are inaccurate and overtreatment is common for these patients, who in reality may have either an aggressive tumor needing immediate intervention, or an indolent tumor that can be managed by active surveillance. There is an urgent need for new molecular biomarkers that can improve risk stratifications for patients with early stage prostate cancer, in order to guide more personalized treatment decisions.","[{'e1': 'extensive use of prostate-specific antigen testing', 'e2': 'detection rates ', 'relation': ' has increased ', 'condition': 'for early stage tumors'}]"
263,P183P6,"MicroRNAs comprise a large class of regulatory noncoding RNAs of approximately 22 nucleotides that control gene expression by binding to partially complementary sequences in target mRNAs, leading to gene silencing. It has been estimated that 60% of all human mRNAs are regulated by miRNAs, which thereby influence key cellular processes such as differentiation and proliferation. Furthermore, miRNAs constitute a particularly attractive source for biomarker discovery, as they are more stable than mRNAs and thus easier to extract and quantify from, for example, formalin-fixed and paraffin-embedded patient tissue samples that have been stored for several years in pathology archives. Although single miRNAs have shown promising potential as diagnostic biomarkers for prostate cancer, current evidence suggests that single miRNAs have suboptimal prognostic potential for prostate cancer when compared with multi-miRNA signatures. Ratio-based miRNA models could be particularly useful, as their design precludes the need for additional normalization factors.","[{'e1': 'MicroRNAs ', 'e2': 'gene expression', 'relation': 'control ', 'condition': ' by binding to partially complementary sequences in target mRNAs'}, {'e1': 'single miRNAs ', 'e2': ' diagnostic biomarkers ', 'relation': 'have shown promising potential as', 'condition': 'for prostate cancer'}]"
264,P183P8,"In summary, the new 4-miRNA prognostic model MiCaP independently predicted biochemical recurrence in three distinct radical prostatectomy cohorts, and was a significant predictor of prostate cancer-specific survival in a radical prostatectomy cohort comprising 352 patients. Further studies are warranted to assess the true clinical utility of MiCaP for improving risk stratification of clinically localized prostate cancer.","[{'e1': 'MiCaP ', 'e2': 'biochemical recurrence', 'relation': 'independently predicted ', 'condition': ' in three distinct radical prostatectomy cohorts'}, {'e1': 'MiCaP ', 'e2': 'prostate cancer-specific survival ', 'relation': 'was a significant predictor of ', 'condition': 'in a radical prostatectomy cohort comprising 352 patients'}]"
265,P184P11,"We found that a distinct interferon signature that is analogous to the previously described Interferon-related DNA Damage Resistance Signature occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of African-American than European-American men. Furthermore, analysis in The Cancer Genome Atlas showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant that controls production of IFN-λ4, a type-III interferon, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-ΔG allele was significantly associated with IRDS in prostate tumors and overall survival of African-American patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines.","[{'e1': ' increased IRDS in prostate tumors ', 'e2': 'decreased disease-free survival', 'relation': 'is associated with', 'condition': 'in The Cancer Genome Atlas'}, {'e1': ' IFNL4 rs368234815-ΔG allele ', 'e2': 'IRDS ', 'relation': 'was significantly associated with ', 'condition': 'in prostate tumors'}, {'e1': 'IFNL4 overexpression', 'e2': 'IRDS ', 'relation': ' induced ', 'condition': 'in three human prostate cancer cell lines.'}]"
266,P184P12,Our study links a germline variant that controls production of IFN-λ4 to the occurrence of a clinically relevant interferon signature in prostate tumors that may predominantly affect men of African ancestry.,"[{'e1': ' a germline variant that controls production of IFN-λ4 ', 'e2': ' the occurrence of a clinically relevant interferon signature ', 'relation': 'is linked to', 'condition': 'in prostate tumors that may predominantly affect men of African ancestry.'}]"
267,P184P13,"Prostate cancer incidence and mortality rates are highest among men of African ancestry. Environmental exposures and ancestry-specific factors may influence prostate cancer biology and cause a more aggressive disease in these men. We and others described an immune signature that is prevalent in prostate tumors of African-American patients and hypothesized that this signature affects tumor biology. Here, we further investigated this immune signature and discovered an interferon signature in tumors of African-American patients that is analogous to the previously described interferon-related DNA damage resistance signature, also termed IRDS. IRDS includes 49 interferon-stimulated genes that are induced through activation of the JAK-STAT pathway. IRDS was initially identified because of its effects leading to resistance to ionizing radiation. It can be induced by persistent activation of the JAK-STAT pathway by various exogenous and endogenous stimuli that generate an interferon response.","[{'e1': 'Environmental exposures and ancestry-specific factors ', 'e2': 'prostate cancer biology ', 'relation': 'may influence ', 'condition': 'among men of African ancestry'}, {'e1': 'Environmental exposures and ancestry-specific factors ', 'e2': 'a more aggressive disease', 'relation': ' cause ', 'condition': 'among men of African ancestry'}]"
268,P184P14,"All interferons induce sets of interferon-stimulated genes that are overlapping but also distinct. However, among the human interferons, the expression of the recently discovered IFN-λ4, a type-III interferon, is uniquely controlled by genetics. Only carriers of the ΔG allele for the germline variant rs368234815-ΔG/TT in the IFNL4 gene can produce this interferon. This allele is most common in individuals of African ancestry, while it is less common in Europeans and Asians. Moreover, carriers of IFNL4 rs368234815-ΔG have an impaired ability to clear certain viral infections, such as hepatitis C virus, spontaneously or after treatment. One of the mechanisms by which IFN-λ4 renders cells refractory to an antiviral response is the induction of a persistent gene signature that resembles IRDS. Thus, we hypothesized that because IFN-λ4 is produced more commonly in men of African ancestry, it might explain the increased occurrence of IRDS in their tumors, and be of clinical importance. Accordingly, we examined whether IFNL4 rs368234815-ΔG is associated with the development of IRDS in prostate tumors and disease outcomes. Consistent with our hypothesis, we found that IFNL4 rs368234815-ΔG is significantly associated with both the presence of IRDS and an increased all-cause mortality among African-American prostatectomy patients.","[{'e1': 'the expression of IFN-λ4 ', 'e2': 'genetics', 'relation': 'is uniquely controlled by ', 'condition': ' among the human interferons'}, {'e1': 'IFNL4 rs368234815-ΔG', 'e2': 'the presence of IRDS ', 'relation': ' is significantly associated with ', 'condition': ' among African-American prostatectomy patients.'}, {'e1': 'IFNL4 rs368234815-ΔG', 'e2': 'an increased all-cause mortality', 'relation': ' is significantly associated with ', 'condition': ' among African-American prostatectomy patients.'}]"
269,P185P1,"We report here numerous novel genes and multiple new signatures which robustly predict prostate cancer recurrence. We extracted 696 differentially expressed genes relative to a reported prostate cancer signature from the TCGA dataset and built a 15-gene signature using Elastic-net with 10-fold cross-validation through analyzing their expressions at 1.5 standard deviation below and 2 standard deviations above a population mean. The signature predicts biochemical recurrence following surgery with 56.4% sensitivity, 72.6% specificity, and 63.24 median months disease free. The prediction accuracy is improved with the use of the signature cutpoint and is further enhanced when all 15 genes were analyzed through their cutpoints instead of their standard deviations. These genes individually associate with biochemical recurrence using either standard deviation or cutpoint as the cutoff points. Eight of 15 genes are individual risk factors after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. Eleven of 15 genes are novel to prostate cancer. The signature discriminates biochemical recurrence with time-dependent AUC values of 76.6% at 11.5 months, 73.8% at 22.3 months, 78.5% at 32.1 months, and 76.4% at 48.4 months. The signature is correlated with adverse features of prostate cancer, high Gleason scores, and advanced tumor stages. The signature remains an independent risk factor of biochemical recurrence after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. In an independent prostate cancer cohort, these 15 genes were altered in prostate cancer versus normal tissue, metastatic prostate cancers versus primary prostate cancers, and recurrent prostate cancers versus nonrecurrent prostate cancers. Importantly, a 10-gene subsignature predicts biochemical recurrence in both the independent cohort and TCGA; this subsignature discriminates biochemical recurrence at 18.4 months with time-dependent AUC of 82.5%. Collectively, our analyses support this signature as a novel and robust signature in predicting biochemical recurrence of prostate cancer.","[{'e1': ' The signature ', 'e2': 'biochemical recurrence ', 'relation': 'predicts ', 'condition': 'following surgery with 56.4% sensitivity, 72.6% specificity, and 63.24 median months disease free'}, {'e1': ' These genes ', 'e2': ' biochemical recurrence', 'relation': 'individually associate with', 'condition': ' using either standard deviation or cutpoint as the cutoff points'}, {'e1': 'The signature ', 'e2': 'biochemical recurrence ', 'relation': 'remains an independent risk factor of ', 'condition': 'after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage'}, {'e1': 'a 10-gene subsignature', 'e2': 'biochemical recurrence', 'relation': ' predicts ', 'condition': ' in both the independent cohort and TCGA'}, {'e1': ' this subsignature ', 'e2': 'biochemical recurrence ', 'relation': 'discriminates ', 'condition': 'at 18.4 months with time-dependent AUC of 82.5%'}]"
270,P185P2,"Prostate cancer is the most common malignancy in men in the developed countries. The disease progresses with a large degree of disparity. While a large proportion of the low grade tumors are not life-threatening, approximately 30% of patients after radical prostatectomy will experience disease recurrence with a rise in serum prostate-specific antigen; this biochemical recurrence indicates significantly increased risk for prostate cancer metastasis and castration-resistant prostate cancer. Metastasis is the leading cause of prostate cancer death. The standard treatment for metastatic prostate cancer is androgen deprivation therapy, which offers palliative care as resistance in the form of castration-resistant prostate cancer always occurs. In this regard, intervention at the point of biochemical recurrence will be more effective than at time when prostate cancer has advanced to later stages. Thus, effectively assessing prostate cancers with increased risk of biochemical recurrence is highly desirable.","[{'e1': 'approximately 30% of patients', 'e2': 'disease recurrence with a rise in serum prostate-specific antigen', 'relation': ' will experience ', 'condition': 'after radical prostatectomy'}]"
271,P185P3,"Recent developments have yielded three commercially available mRNA expression-based multigene panels, Oncotype DX, Prolaris, and Decipher. Both the 17-gene Oncotype DX and the 31-gene Prolaris improve risk stratification of patients with high risk of prostate cancer recurrence at time of diagnosis and after radical prostatectomy. The 22-gene Decipher predicts metastasis following radical prostatectomy. While these and other biomarkers assist decision making and thus improve patient management, their clinical application requires further validation. There is a clear need to improve our ability to stratify prostate cancers with high risk of recurrence following radical prostatectomy. The challenge in accurately predicting prostate cancer recurrence is in part attributable to a complex network of pathways that drive the disease development.","[{'e1': 'The 22-gene Decipher ', 'e2': 'metastasis ', 'relation': 'predicts ', 'condition': 'following radical prostatectomy'}]"
272,P185P4,"The Mucin 1 network plays a role in biochemical recurrence after radical prostatectomy. Mucin 1 is a tumor-associated antigen that has been intensively investigated. Mucin 1 is a glycoprotein that is expressed on the apical surface of most epithelial tissues; its glycosylation is altered in over 70% of cancers. In prostate cancer, Mucin 1 expression is upregulated and aberrantly glycosylated. These abnormalities are associated with angiogenesis and adverse clinical features. Mucin 1 upregulation weakly correlates with shortening in disease-free survival and overall survival and associates with adverse histopathology following radical prostatectomy. A 3-protein panel is related to poor prognosis in men with local prostate cancer. Increases in Mucin 1 mRNA expression were detected in metastatic prostate cancer. Genomic alterations in a 25-gene Mucin 1 network were marginally associated with prostate cancer recurrence. Among these 25 genes, genomic alterations in nine genes substantially enhanced the association.","[{'e1': 'The Mucin 1 network ', 'e2': 'biochemical recurrence ', 'relation': 'plays a role in ', 'condition': 'after radical prostatectomy'}, {'e1': 'Mucin 1 upregulation ', 'e2': 'shortening ', 'relation': 'weakly correlates with ', 'condition': 'in disease-free survival and overall survival '}, {'e1': 'Mucin 1 upregulation ', 'e2': 'adverse histopathology ', 'relation': 'associates with ', 'condition': 'following radical prostatectomy'}, {'e1': ' A 3-protein panel ', 'e2': 'poor prognosis', 'relation': 'is related to ', 'condition': ' in men with local prostate cancer.'}]"
273,P185P5,"To further explore the biomarker value of the Mucin 1 network, we examined the transcriptome of the 9-gene Mucin 1 genomic signature using the TCGA Provisional dataset within cBioPortal, and established 696 differentially expressed genes. From these differentially expressed genes, a 15-gene panel and multiple subpanels were constructed. These signatures robustly associate with reductions in disease-free survival following radical prostatectomy in two independent prostate cancer datasets. Cutpoints have been derived, which not only enhance the power of these signatures in the stratification of men with higher risk of biochemical recurrence but also provide a guideline for the subsequent validation and clinical application. Taken together, we have constructed a set of novel and robust signatures to assess prostate cancer recurrence following radical prostatectomy.","[{'e1': 'These signatures ', 'e2': ' reductions in disease-free survival', 'relation': 'robustly associate with', 'condition': ' following radical prostatectomy in two independent prostate cancer datasets'}]"
274,P185P6,"We have formulated a novel strategy to derive differentially expressed genes relative to a reported prostate cancer signature from the most comprehensive and large prostate cancer genomic dataset and to systemically analyze these differentially expressed genes for pathways affected and impacts on prostate cancer recurrence. In this effort, a novel multigene set has been constructed. The signature robustly predicts prostate cancer recurrence and is an independent risk factor of prostate cancer recurrence after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. Among these 15 component genes include 5 candidate oncogenic genes and 6 novel prostate cancer genes; within these 11 novel genes affecting prostate cancer recurrence, 6 genes individually predict prostate cancer recurrence after adjusting for the above clinical factors. Collectively, we have identified novel genes affecting oncogenesis in general and prostate cancer pathogenesis in particular as well as constructed a novel and robust multigene set predicting prostate cancer recurrence using our system reported here. This system will have applications in exploration of publicly available datasets for factors affecting cancer progression.","[{'e1': 'The signature ', 'e2': 'prostate cancer recurrence ', 'relation': 'is an independent risk factor of ', 'condition': 'after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage.'}, {'e1': ' 6 genes ', 'e2': 'prostate cancer recurrence', 'relation': 'individually predict ', 'condition': ' after adjusting for the above clinical factors'}]"
275,P186P1,"Radiotherapy is the standard treatment option for advanced prostate cancer. Unfortunately, despite significant advances in radiation delivery, prostate cancer radioresistance occurs in a large proportion of patients undergoing radiotherapy. As a way to enhance radiotherapy effectiveness, research advances into the mechanisms regulating the immune response have revived interest in combination radiation and immune-based therapies. Methods: miR-195/-16 family and PD-L1 levels were analyzed in samples from a GSE21032 data set. Kaplan-Meier analysis was used to evaluate the difference in biochemical recurrence-free survival associated with miR-195 and miR-16 expression. qRT-PCR and western blot were used to evaluate the miR-195, miR-16 and PD-L1 expression. Then, we used bioinformatics analysis and luciferase reporter assay to predict and confirm the miR-195 and miR-16 target gene. Finally, we elucidated the miR-195 and miR-16 function on immune evasion in the DU145/T cell co-culture model and syngeneic mouse model treated with radiation through qRT-PCR, western blot, flow cytometry and ELISA. Results: High levels of miR-195 and miR-16 were positively correlated with the biochemical recurrence-free survival of prostate cancer patients. miR-195 and miR-16 were inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. Further mechanistic investigations revealed that miR-195 and miR-16 inhibited PD-L1 expression. Additionally, restoration of miR-195 and miR-16 expression enhanced radiotherapy via T cell activation in the tumor microenvironment by blocking PD-L1 expression. This synergistic effect of immunotherapy and radiotherapy was associated with the proliferation of functional cytotoxic CD8+ T cells and inhibition of myeloid-derived suppressor cells and regulatory T cells. Conclusions: Our data reveal biological and functional interactions between immunotherapy and radiotherapy through the miR-195/-16 family regulatory cascade.","[{'e1': 'restoration of miR-195 and miR-16 expression ', 'e2': 'radiotherapy ', 'relation': 'enhanced ', 'condition': 'via T cell activation in the tumor microenvironment by blocking PD-L1 expression'}]"
276,P186P3,"The immune response affects cancer development by acting as an extrinsic tumor suppressor that restrains tumor expansion or destroys tumors. However, tumor cells can escape immune surveillance. T-lymphocyte associated antigen-4 and programmed death-1 are the two immunoregulatory proteins expressed on T cell membranes. CD80, the CTLA-4 receptor ligand, is expressed in dendritic cells, whereas PD-L1, the PD-1 ligand, is expressed in tumor and or macrophage cells. The interactions of CD80 with CTLA-4 and of PD-L1 with PD-1 inhibit CD8+ cytotoxic T lymphocyte survival and proliferation and affect the function of tumor-infiltrating T cells, ultimately suppressing the immune response and inducing immune tolerance of cancer. Radiotherapy exerts some potentially anti-therapeutic effects by inducing tumor cells that express PD-L1, secrete TGF-β, and induce regulatory T cells. These findings suggest a potential link between radiotherapy and immunoresistance in prostate cancer.","[{'e1': 'The immune response ', 'e2': 'cancer development ', 'relation': 'affects ', 'condition': 'by acting as an extrinsic tumor suppressor that restrains tumor expansion or destroys tumors. However, tumor cells can escape immune surveillance'}, {'e1': 'Radiotherapy ', 'e2': 'some potentially anti-therapeutic effects ', 'relation': 'exerts ', 'condition': 'by inducing tumor cells that express PD-L1, secrete TGF-β, and induce regulatory T cells'}, {'e1': 'radiotherapy ', 'e2': 'immunoresistance ', 'relation': 'is potentially linked to ', 'condition': 'in prostate cancer.'}]"
277,P186P4,"miR-195 and miR-16 are members of the miR-15/-16/-195/-424/-497/-503 family. miR-195 and miR-16 overexpression increases radiosensitivity of cancer cells. miR-195 inhibits human prostate cancer progression by targeting RPS6KB1, and miR-16 acts as a tumor suppressor gene in prostate cancer by controlling cell survival, proliferation and invasion via BCL2, CCND1 and WNT3A. However, it is unclear whether the miR-195/-16 family is involved in the regulation of the immune response. In this study, we demonstrated both in vitro and in vivo that restoration of miR-195 and miR-16 expression enhanced radiotherapy via T cell activation in the tumor microenvironment by blocking the PD-L1 immune checkpoint.","[{'e1': 'miR-195 ', 'e2': 'human prostate cancer progression ', 'relation': 'inhibits ', 'condition': 'by targeting RPS6KB1'}, {'e1': 'miR-16 ', 'e2': 'tumor suppressor gene ', 'relation': 'acts as a ', 'condition': 'in prostate cancer '}, {'e1': 'miR-16 ', 'e2': 'tumor suppressor gene in prostate cancer ', 'relation': 'acts as a ', 'condition': 'by controlling cell survival, proliferation and invasion via BCL2, CCND1 and WNT3A'}, {'e1': ' restoration of miR-195 and miR-16 expression ', 'e2': 'radiotherapy ', 'relation': 'enhanced ', 'condition': 'via T cell activation in the tumor microenvironment '}, {'e1': ' restoration of miR-195 and miR-16 expression ', 'e2': 'radiotherapy via T cell activation in the tumor microenvironment ', 'relation': 'enhanced ', 'condition': 'by blocking the PD-L1 immune checkpoint'}]"
278,P186P5,Restoration of the expression of miR-195/-16 could enhance radiotherapy via activation of the T cell response in the tumor microenvironment by blocking the PD-L1 immune checkpoint. This synergy between radiotherapy and immunotherapy was accompanied by the proliferation of functional cytotoxic CD8+ T cells and inhibition of MDSCs and Tregs. This work indicates a biological and functional interaction between immunotherapy and radiotherapy through the miR-195/-16 family regulatory cascade.,"[{'e1': 'Restoration of the expression of miR-195/-16 ', 'e2': 'radiotherapy ', 'relation': 'could enhance ', 'condition': 'via activation of the T cell response in the tumor microenvironment '}, {'e1': 'Restoration of the expression of miR-195/-16 ', 'e2': 'radiotherapy via activation of the T cell response in the tumor microenvironment ', 'relation': 'could enhance ', 'condition': 'by blocking the PD-L1 immune checkpoint'}]"
279,P187P2,"Total RNA was extracted from 212 prostatic tissue samples, 101 benign prostatic hyperplasia and 111 prostate cancer, and, following cDNA synthesis, quantitative real-time PCR was performed for the expressional quantification of RNase κ. Extensive statistical analysis, including bootstrap resampling, was performed to investigate the differential expression of RNase κ in patients with benign prostatic hyperplasia and prostate cancer and its associations with patients’ clinicopathological and survival data.","[{'e1': ' quantitative real-time PCR ', 'e2': ' the expressional quantification of RNase κ', 'relation': 'was performed for', 'condition': 'following cDNA synthesis'}]"
280,P187P3,RNase κ was significantly downregulated in prostate cancer patients compared to benign prostatic hyperplasia ones. RNase κ overexpression was associated with decreased risk of prostate cancer development and can discriminate between prostate cancer and benign prostatic hyperplasia independently of serum PSA levels. RNase κ upregulation was also associated with less advanced and less aggressive tumors as well as with longer progression-free survival. Finally univariate bootstrap Cox regression confirmed that RNase κ was associated with favorable prognosis.,"[{'e1': ' RNase κ overexpression ', 'e2': ' prostate cancer and benign prostatic hyperplasia ', 'relation': 'can discriminate between', 'condition': 'independently of serum PSA levels'}]"
281,P187P4,"RNase κ is a biomarker of favorable prognosis in prostate cancer, which is significantly associated with less advanced and aggressive disease, as well as with enhanced progression-free survival.","[{'e1': 'RNase κ ', 'e2': 'favorable prognosis ', 'relation': 'is a biomarker of ', 'condition': 'in prostate cancer'}]"
282,P187P7,"Human RNase κ is an endoribonuclease, coding by a gene that consists of three exons and two intervening introns. Recently, our group demonstrated that RNase κ is subjected to alternative splicing, within the first intron, producing two transcript variants, RNase κ-01 and RNase κ-02, which code for two structurally different protein isoforms. The high percentage of amino acid conservation of human RNase κ along with its expression in a wide spectrum of tissues and developmental stages, denote its significant, but yet largely obscure, biological function. Moreover, RNase κ exhibits increased or decreased expression levels in several cancer types, suggesting its possible clinical utility as molecular cancer marker.","[{'e1': 'RNase κ ', 'e2': 'increased or decreased expression levels ', 'relation': 'exhibits ', 'condition': 'in several cancer types'}]"
283,P187P9,"PSA still remains the cornerstone in prostate cancer screening, prognosis and treatment monitoring. However, its low diagnostic specificity and its inadequacy to discriminate clinically indolent from aggressive tumors have lead to overdiagnosis and overtreatment and consequently to incalculable physiological and psychological burden for the patients and to increased financial costs for the healthcare systems. The present study provides evidence that RNase κ mRNA levels, assayed by a cost-effective, non-laborious and specific PCR-based methodology, may aid in prostate cancer diagnosis and more importantly in improving outcome prediction for prostate cancer patients.","[{'e1': ' RNase κ mRNA levels ', 'e2': ' outcome prediction ', 'relation': 'may aid in improving', 'condition': 'for prostate cancer patients.'}]"
284,P188P1,"The identification of new molecular targets and biomarkers associated with high risk of recurrence and response to therapy represents one of the main clinical challenges in the management of advanced disease in endometrial cancer. In this sense, the field of liquid biopsy has emerged as a great revolution in oncology and is considered the way to reach personalised medicine. In this review, we discuss the promising but already relatively limited advances of liquid biopsy in endometrial cancer compared to other types of tumours like breast, colorectal or prostate cancer. We present recent data analysing circulating tumour material in minimally-invasive blood samples, but also in alternative forms of liquid biopsy like uterine aspirates. Proteomic and genomic studies focused on liquid-based uterine samples are resulting not only in optimal diagnostic tools but also in reliable approaches to address tumour heterogeneity. Likewise, circulating tumour cells and circulating tumour DNA represent an opportunity for the correct stratification of patients, for the assessment of early recurrent disease or for the real-time monitoring of therapy responses. Appropriately designed studies and implementation in clinical trials will determine the value of liquid biopsy for precision oncology in endometrial cancer.","[{'e1': 'The identification of new molecular targets and biomarkers ', 'e2': ' one of the main clinical challenges ', 'relation': 'represents', 'condition': 'in the management of advanced disease in endometrial cancer'}, {'e1': 'Appropriately designed studies and implementation in clinical trials ', 'e2': 'the value of liquid biopsy ', 'relation': 'will determine ', 'condition': 'for precision oncology in endometrial cancer.'}]"
285,P188P2,"Endometrial cancer is the fourth leading cancer in women from developed countries. In Europe, the number of new cases was about 100,000 in 2012, with an incidence of 13.6 per 100,000 women. This tumour originates in the inner layer of the uterus when epithelial cells lining the myometrium start to proliferate abnormally. Although most endometrial cancers are diagnosed early, mainly due to symptomatic postmenopausal metrorrhagia, up to 20% of the lesions progress to a high-stage carcinoma. Unfortunately, the five-year survival in this group of women drops to 15%, compared to 90% in women diagnosed with confined disease. Myometrial infiltration and the appearance of disseminated aggressive tumour cells are crucial events for prognosis and death in endometrial cancer. Surgery represents the primary treatment. In addition, patients with high risk of recurrence also receive adjuvant radiotherapy, together with chemotherapy that is restricted to metastatic recurrent disease and high-grade endometrial cancers. However, traditional chemotherapy regimens are less effective in comparison with other cancers. This overview situates the clinical challenge on the identification of new molecular targets and biomarkers associated with a high risk of recurrence and or with response to therapy as valuable tools to improve our management of advanced disease in endometrial cancer.","[{'e1': 'This tumour ', 'e2': 'the inner layer of the uterus ', 'relation': 'originates in ', 'condition': 'when epithelial cells lining the myometrium start to proliferate abnormally'}]"
286,P188P6,"The analysis of these different types of liquid biopsy has been successfully applied in oncology research during the last two decades, closely linked to the development of ultrasensitive methods for their detection. In fact, the main limitation to working with liquid biopsy is the low quantity of tumour material present in circulation. For example, in metastatic patients, the mean circulating tumour cell level is 1 circulating tumour cell per 10^6 to 10^8 mononuclear cells, while circulating tumour DNA is normally less than 0.01%. Fortunately, nowadays we have highly sensitive techniques to tackle liquid biopsy analyses with enough guarantees.","[{'e1': 'The analysis of these different types of liquid biopsy ', 'e2': 'oncology research', 'relation': 'has been successfully applied in ', 'condition': ' during the last two decade'}]"
287,P188P7,"Circulating tumour cell research is considered the start-point of the liquid biopsy field. Early in the formation and growth of a primary tumour, cells are released into the bloodstream. Several groups are studying the clinical benefit of circulating tumour cell monitoring. Circulating tumour cells have been validated as a prognostic marker in metastatic breast cancer and other solid tumours such as prostate, colorectal, and lung cancer, showing even more accuracy than conventional imaging methods for response evaluation. However, there are still technological challenges to use circulating tumour cell monitoring to detect minimal residual disease in patients at early stages. On the other hand, the molecular characterisation of circulating tumour cells is of great value to guide the selection of targeted therapies since it allows clinicians to have a dynamic view of different molecular targets such as ERBB2, EGFR, AR or PD-L1, among others.","[{'e1': 'Circulating tumour cells ', 'e2': 'a prognostic marker ', 'relation': 'have been validated as ', 'condition': 'in metastatic breast cancer '}, {'e1': 'Circulating tumour cells ', 'e2': 'a prognostic marker ', 'relation': 'have been validated as ', 'condition': 'in other solid tumours such as prostate, colorectal, and lung cancer'}]"
288,P188P8,"Despite all the studies demonstrating the relevance of circulating tumour cells for cancer management, the results from clinical trials have failed to demonstrate a clear clinical benefit. In comparison, the younger brother of circulating tumour cells, the circulating tumour DNA, has already been implemented in routine clinical practice after European Medicines Agency approval of the EGFR mutation test in plasma of patients with non-small cell lung cancer. Highly sensitive and specific methods have been developed to detect circulating tumour DNA, including beads, emulsion, amplification and magnetics based digital PCR, safe sequencing, tagged amplicon deep sequencing, and digital PCR to detect point mutations or whole-genome sequencing. Using these technologies, several studies have demonstrated that circulating tumour DNA may be a useful tool for drug development and for the study of intratumour heterogeneity and clonal evolution in tumours such as breast, colon, melanoma and non-small cell lung cancer. In gynaecological tumours, and especially for ovarian cancer, tagged amplicon deep sequencing has demonstrated high sensitivity to detect point mutations.","[{'e1': ' tagged amplicon deep sequencing ', 'e2': 'high sensitivity to detect point mutations.', 'relation': 'has demonstrated ', 'condition': 'In gynaecological tumours, and especially for ovarian cancer'}]"
289,P189P5,This study suggests that TTP RNA expression can be used to enhance the accuracy of CAPRA-S to predict outcomes in patients treated with RP.,"[{'e1': 'TTP RNA expression', 'e2': 'the accuracy of CAPRA-S ', 'relation': ' can be used to enhance ', 'condition': 'to predict outcomes in patients treated with RP.'}]"
290,P189P7,"Tristetraprolin (TTP, ZFP36), an RNA-binding protein involved in controlling mRNA stability, impairs tumor growth and development in a variety of malignancies, including prostate cancer. In a previous study that established TTP’s functions as a tumor suppressor in prostate cancer, analysis of TTP RNA expression in a single prostate cancer patient dataset suggested that low TTP-expressing primary tumors may have increased rates of biochemical recurrence compared to high TTP-expressing prostate cancer. To more fully assess whether TTP is a prognostic biomarker that identifies prostate cancer patients with an increased risk of poor clinical outcomes, we evaluated two prostate cancer patient cohorts from Moffitt Cancer Center for TTP RNA or TTP protein expression, as well as six independent prostate cancer genomic datasets having post-surgical clinical follow-up from multiple medical institutions. Our findings establish that TTP alone is a clinically relevant prostate cancer biomarker that provides an improvement over clinical and pathologic variables to predict which patients may harbor aggressive disease.","[{'e1': 'Tristetraprolin (TTP, ZFP36) ', 'e2': 'tumor growth and development ', 'relation': 'impairs ', 'condition': 'in a variety of malignancies, including prostate cancer'}]"
291,P189P8,"In conclusion, the tumor suppressor TTP is a clinically relevant prognostic prostate cancer biomarker that could be used in determining which patients will have poor clinical outcomes at the time of RP, and may improve the effectiveness of CAPRA-S. Notably, TTP performs particularly well as a biomarker in low-grade prostate cancer patients where much controversy exists on appropriate management options. The ability to use TTP to more accurately identify clinically low-risk patients who may harbor aggressive disease will enable physicians to more accurately risk-stratify their patients for appropriate therapy recommendations and will prevent overtreatment of potentially indolent disease.","[{'e1': 'TTP ', 'e2': 'a biomarker ', 'relation': 'performs particularly well as ', 'condition': 'in low-grade prostate cancer patients where much controversy exists on appropriate management options'}]"
292,P18P1,A substantial number of patients diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients at the highest risk to guide therapy intensification.,"[{'e1': 'A substantial number of patients diagnosed with high-risk prostate cancer', 'e2': ' metastatic progression ', 'relation': ' are at risk for', 'condition': 'after primary treatment'}]"
293,P18P10,"Our novel patient-level DDR pathway profiling approach revealed distinct DDR pathway clusters and demonstrated that the DDR pathway profiles have prognostic association with metastatic progression and overall survival. Thus, DDR pathway profiling may be useful for identifying prostate cancer patients who have increased risk of metastatic progression after radical prostatectomy. As a biomarker of disease progression, DDR pathway profiling may be used to select patients for earlier treatment intensification with approaches such as adjuvant radiation or systemic therapy and may represent an avenue toward improved personalization of therapy for prostate cancer patients.","[{'e1': 'DDR pathway profiling ', 'e2': 'identifying prostate cancer patients who have increased risk of metastatic progression ', 'relation': 'may be useful for ', 'condition': 'after radical prostatectomy'}]"
294,P18P5,"Across the training cohort and pooled validation cohorts, 1090 men were studied; mean (SD) age at diagnosis was 65.3 (6.4) years. We found that there are distinct clusters of DDR pathways within the cohort, and DDR pathway enrichment is only weakly correlated with clinical variables such as age (Spearman ρ [ρ], range, −0.07 to 0.24), Gleason score (ρ, range, 0.03 to 0.20), prostate-specific antigen level (ρ, range, −0.07 to 0.10), while 13 of 17 DDR gene sets are strongly correlated with androgen receptor pathway enrichment (ρ, range, 0.33 to 0.82). In published cohorts, DDR pathway genes are rarely mutated. A DDR pathway profile prognostic signature built in the training cohort was significantly associated with biochemical recurrence-free, metastasis-free, and overall survival in the pooled validation cohorts independent of standard clinicopathological variables. The prognostic performance of the signature for metastasis-free survival appears to be stronger in the younger patients (HR, 1.67; 95% CI, 1.12–2.50) than in the older patients (HR, 0.77; 95% CI, 0.29–2.07) on multivariate Cox analysis.","[{'e1': 'DDR pathway genes ', 'e2': 'mutated', 'relation': 'are rarely ', 'condition': 'In published cohorts'}, {'e1': ' A DDR pathway profile prognostic signature built in the training cohort ', 'e2': 'biochemical recurrence-free ', 'relation': 'was significantly associated with ', 'condition': 'in the pooled validation cohorts independent of standard clinicopathological variables'}, {'e1': ' A DDR pathway profile prognostic signature built in the training cohort ', 'e2': 'metastasis-free', 'relation': 'was significantly associated with ', 'condition': 'in the pooled validation cohorts independent of standard clinicopathological variables'}, {'e1': ' A DDR pathway profile prognostic signature built in the training cohort ', 'e2': 'overall survival ', 'relation': 'was significantly associated with ', 'condition': 'in the pooled validation cohorts independent of standard clinicopathological variables'}, {'e1': 'The prognostic performance ', 'e2': 'metastasis-free survival appears to be stronger', 'relation': 'of the signature for ', 'condition': ' in the younger patients than in the older patients '}]"
295,P18P9,"We hypothesized that DNA damage and repair (DDR) pathways hold prognostic information in prostate cancer and developed a novel patient-level DDR pathway profiling approach to investigate this. We applied this approach to a large prostatectomy cohort with long clinical follow-up that allows for analysis of robust outcomes of biochemical recurrence-free, metastasis-free, and overall survival. We assessed correlation between DDR pathways and molecular or clinical variables and used multivariate analysis to build and validate a prognostic signature biomarker combining the DDR pathways. Overall, this study investigates the potential for individualized DDR pathway profiling in the clinical management of prostate cancer.","[{'e1': 'this study ', 'e2': ' individualized DDR pathway profiling ', 'relation': 'investigates the potential for', 'condition': 'in the clinical management of prostate cancer.'}]"
296,P190P2,"TTP RNA expression was measured in an radical prostatectomy cohort of patients treated at Moffitt Cancer Center and obtained from six publicly available radical prostatectomy datasets with biochemical recurrence and or metastatic outcome data. TTP protein expression was measured by immunohistochemistry in a tissue microarray of 153 Moffitt Cancer Center radical prostatectomy samples. The time to biochemical recurrence or metastasis based on TTP RNA or protein levels was calculated using Kaplan-Meier analysis. Univariable and multivariable Cox proportional hazard models were performed on multiple cohorts to evaluate if TTP is a clinically relevant biomarker, and to assess if TTP improves upon the Cancer of the Prostate Risk Assessment postsurgical score for predicting clinical outcomes.","[{'e1': 'TTP protein expression ', 'e2': 'immunohistochemistry', 'relation': 'was measured by ', 'condition': ' in a tissue microarray of 153 Moffitt Cancer Center radical prostatectomy samples'}]"
297,P190P3,"In all of the radical prostatectomy patient cohorts, prostate cancer with low TTP RNA or protein levels had decreased time to biochemical recurrence or metastasis versus TTP-High tumors. Further, the decreased time to biochemical recurrence in TTP-Low prostate cancer was more pronounced in low-grade tumors. Finally, pooled survival analysis suggests that TTP RNA expression provides independent information beyond CAPRA-S to predict biochemical recurrence.","[{'e1': ' prostate cancer with low TTP RNA or protein levels ', 'e2': 'time to biochemical recurrence or metastasis versus TTP-High tumors.', 'relation': 'had decreased ', 'condition': 'In all of the radical prostatectomy patient cohorts'}]"
298,P190P5,This study suggests that TTP RNA expression can be used to enhance the accuracy of CAPRA-S to predict outcomes in patients treated with radical prostatectomy.,"[{'e1': 'TTP RNA expression ', 'e2': 'the accuracy of CAPRA-S', 'relation': 'can be used to enhance ', 'condition': ' to predict outcomes in patients treated with radical prostatectomy.'}]"
299,P190P7,"Tristetraprolin, an RNA-binding protein involved in controlling mRNA stability, impairs tumor growth and development in a variety of malignancies, including prostate cancer. In a previous study that established TTP’s functions as a tumor suppressor in prostate cancer, analysis of TTP RNA expression in a single prostate cancer patient dataset suggested that low TTP-expressing primary tumors may have increased rates of biochemical recurrence compared to high TTP-expressing prostate cancer. To more fully assess whether TTP is a prognostic biomarker that identifies prostate cancer patients with an increased risk of poor clinical outcomes, we evaluated two prostate cancer patient cohorts from Moffitt Cancer Center for TTP RNA or TTP protein expression, as well as six independent prostate cancer genomic datasets having post-surgical clinical follow-up from multiple medical institutions. Our findings establish that TTP alone is a clinically relevant prostate cancer biomarker that provides an improvement over clinical and pathologic variables to predict which patients may harbor aggressive disease.","[{'e1': 'Tristetraprolin ', 'e2': ' tumor growth and development ', 'relation': 'impairs', 'condition': 'in a variety of malignancies, including prostate cancer'}]"
300,P190P8,"In conclusion, the tumor suppressor TTP is a clinically relevant prognostic prostate cancer biomarker that could be used in determining which patients will have poor clinical outcomes at the time of radical prostatectomy, and may improve the effectiveness of CAPRA-S. Notably, TTP performs particularly well as a biomarker in low-grade prostate cancer patients where much controversy exists on appropriate management options. The ability to use TTP to more accurately identify clinically low-risk patients who may harbor aggressive disease will enable physicians to more accurately risk-stratify their patients for appropriate therapy recommendations and will prevent overtreatment of potentially indolent disease.","[{'e1': ' TTP ', 'e2': 'a biomarker', 'relation': 'performs particularly well as ', 'condition': ' in low-grade prostate cancer patients where much controversy exists on appropriate management options'}]"
301,P191P1,"Prostate cancer (PCa) is one of the most prevalent cancer types in men. Biochemical recurrence continues to occur in a large proportion of patients after radical prostatectomy. Thus, prognostic biomarkers are required to determine which treatment is suitable. In the present study, RNA-sequencing gene expression data from The Cancer Genome Atlas was used in order to develop a risk-score staging system based on the expression of eight genes. Cox multivariate regression was used to predict the outcome of patients with PCa. The biochemical recurrence-free survival of patients with low-risk scores was significantly longer compared with patients with high-risk scores. This result was further validated using another dataset, GSE70769, from the National Center for Biotechnology Information. The prognostic values of other clinical information and risk scores were evaluated for 5-year biochemical recurrence. The prognostic value of the risk score was determined using an area under curve value of 0.819, predicting the 5-year biochemical recurrence of patients with PCa. The risk score was identified to be significantly associated with primary tumor stage, Gleason score, and lymph node invasion, but was independent of age. Cox multivariate regression revealed that the risk score was an indicator for prediction of biochemical recurrence. Thus, the risk score is a valuable and robust indicator for predicting the biochemical recurrence of patients with PCa.","[{'e1': ' Biochemical recurrence ', 'e2': 'a large proportion of patients ', 'relation': 'continues to occur in ', 'condition': 'after radical prostatectomy'}, {'e1': ' RNA-sequencing gene expression data from The Cancer Genome Atlas ', 'e2': 'a risk-score staging system ', 'relation': 'was used in order to develop ', 'condition': 'based on the expression of eight genes'}]"
302,P191P2,"Prostate cancer (PCa) is one of the most prevalent cancer types in men; in 2015, there were 60,300 newly diagnosed cases of PCa in China, resulting in 26,000 mortalities. Disease recurrence has been reported in a large proportion of patients following radical prostatectomy, and castration-resistant disease typically develops as a result. Although prognostic and clinical indicators were implemented, the prognostic effect was not fully understood. Thus, clinical biomarkers for PCa biochemical recurrence are required. Huang et al used long non-coding RNAs to develop a prediction model for biochemical recurrence; however, the analysis lacked validation datasets.","[{'e1': 'Disease recurrence ', 'e2': 'a large proportion of patients ', 'relation': 'has been reported in ', 'condition': 'following radical prostatectomy'}]"
303,P192P1,"Pentatricopeptide repeat domain protein 3 (PTCD3) is a mitochondrial RNA-binding protein that serves a role in mitochondrial translation. PTCD3 was originally reported as an oncogene that is involved in breast cancer and lymphoma. However, the expression and function of PTCD3 in prostate cancer (PCa) are unknown. Therefore, the aim of the present study was to investigate the expression of PTCD3 and its clinical significance in PCa. Immunohistochemistry and dataset analyses revealed that PTCD3 protein expression levels were enhanced in human PCa tissues and mouse PCa models. PTCD3 expression levels were positively correlated with advanced PCa pathological grade and clinical stage. Additionally, PTCD3 mRNA expression was positively correlated with tissue malignancy, high Gleason score and distant metastasis in The Cancer Genome Atlas dataset. Kaplan-Meier analysis revealed that high PTCD3 levels can predict the increased biochemical recurrence (BCR)-free survival in all patients with or without metastasis. The overexpression of PTCD3 could be used as an independent prognostic marker of poor BCR-free survival. Immunofluorescence and western blot analysis in human PCa cell lines further confirmed that PTCD3 levels were associated with the hormone independence of PCa. Therefore, the present study revealed that PTCD3 levels may serve as a novel biomarker for PCa prognosis.","[{'e1': 'PTCD3 mRNA expression ', 'e2': 'tissue malignancy', 'relation': 'was positively correlated with ', 'condition': 'in The Cancer Genome Atlas dataset'}, {'e1': 'PTCD3 mRNA expression ', 'e2': ' high Gleason score ', 'relation': 'was positively correlated with ', 'condition': 'in The Cancer Genome Atlas dataset'}, {'e1': 'PTCD3 mRNA expression ', 'e2': 'distant metastasis ', 'relation': 'was positively correlated with ', 'condition': 'in The Cancer Genome Atlas dataset'}, {'e1': 'high PTCD3 levels ', 'e2': 'increased biochemical recurrence (BCR)-free survival ', 'relation': 'can predict the ', 'condition': 'in all patients with or without metastasis'}, {'e1': 'PTCD3 levels ', 'e2': 'a novel biomarker ', 'relation': 'may serve as ', 'condition': 'for PCa prognosis.'}]"
304,P192P2,"Prostate cancer (PCa) is the most commonly diagnosed male cancer in Western countries and the second leading cause of death in the US. Approximately 164,690 people are diagnosed with PCa, which cause approximately 9% of cancer-related deaths among American men. PCa is a heterogeneous and multi-focal cancer with highly variable natural history, causing difficulty in predicting its initiation, progression and prognosis. The combination of Gleason score, TNM stage, lymph node status and serum prostate-specific antigen (PSA) level has been commonly used to predict the prognosis of patients with PCa. PSA testing is widely used for the early clinical diagnosis of PCa, but its true value remains controversial because of its poor tumour specificity. According to statistics, PSA testing may have led to false positives in 23-42% of all diagnosed cases; furthermore, the patients receiving treatments, such as radical prostatectomy or radiotherapy, must pay substantial costs and subject themselves to serious side effects. Approximately 25% of patients with PCa suffer from biochemical recurrence (BCR) following radical prostatectomy. Therefore, identifying methods that can be used to correctly distinguish indolent and aggressive cancers and finding novel and effective biomarkers are critical to improve the understanding of the biological progression of PCa and to advance the diagnosis and prognosis of PCa in clinics.","[{'e1': 'Approximately 25% of patients with PCa ', 'e2': ' biochemical recurrence (BCR) ', 'relation': 'suffer from', 'condition': 'following radical prostatectomy'}]"
305,P192P5,"In conclusion, our data strongly suggested that PTCD3 overexpression may play an important role in the characteristics and aggressive behaviour of PCa, especially in groups with advanced pathological or clinical stage and high Gleason score. Additionally, PTCD3 upregulation is associated with poor prognosis in patients with PCa. This protein may be a novel prognostic biomarker for PCa and a potential therapeutic target for patients with PCa. However, further study is necessary to gain a full understanding of the underlying molecular mechanisms.","[{'e1': 'PTCD3 upregulation ', 'e2': 'poor prognosis ', 'relation': 'is associated with ', 'condition': 'in patients with PCa'}]"
306,P193P2,"Prostate cancer remains a major clinical burden, being the most prevalent cancer and one of the leading causes of cancer-specific deaths in North American men. It is a clinically heterogeneous disease wherein the majority of cancers display a favorable outcome, while a subset affecting a considerable number of patients progress to metastatic and lethal stage. Radical prostatectomy or radiation therapy is considered the standard primary treatment option for localized prostate cancer and more recently, active surveillance has emerged as a viable alternative for patients presenting favorable clinicopathologic features. One of the key challenges in the clinical management of prostate cancer is to accurately distinguish indolent from aggressive tumors in order to avoid overtreatment of clinically insignificant cancers and undertreatment of tumors with metastatic potential.","[{'e1': 'Radical prostatectomy or radiation therapy', 'e2': 'the standard primary treatment option ', 'relation': ' is considered ', 'condition': 'for localized prostate cancer'}]"
307,P193P4,"Copy number alterations such as deletion of chromosome 10q23 (PTEN) and gain of 16p13.3 (PDPK1) are detected at higher frequency in lymph node metastases than in primary tumors, suggesting a role in prostate cancer progression. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein is a tumor suppressor that negatively regulates the phosphatidylinositol 3-kinase/AKT survival pathway. Encoded by PDPK1, 3-Phosphoinositide-dependent protein kinase-1 (PDK1) phosphorylates and activates the AGC kinase members regulated by phosphatidylinositol 3-kinase, including AKT. In addition to its kinase activity on AKT, our laboratory has shown that PDK1 also has an important role in prostate cancer cell migration. PTEN deletion has been shown to be associated with poor outcome in prostate cancer after radical prostatectomy. Recently, we reported that the 16p13.3 gain was also associated with adverse outcome after radical prostatectomy. In the current study, we demonstrated that the PTEN genomic deletion measured by FISH is a strong independent predictor of poor clinical outcome after radical prostatectomy, including in low-intermediate risk patients and showed that the combination of PTEN deletion and 16p13.3 gain status improved patient risk stratification.","[{'e1': 'Copy number alterations ', 'e2': 'higher frequency', 'relation': 'are detected at ', 'condition': ' in lymph node metastases than in primary tumors'}, {'e1': ' PTEN deletion ', 'e2': ' poor outcome ', 'relation': 'has been shown to be associated with', 'condition': 'in prostate cancer '}, {'e1': ' PTEN deletion ', 'e2': ' poor outcome in prostate cancer ', 'relation': 'has been shown to be associated with', 'condition': 'after radical prostatectomy'}, {'e1': 'PTEN genomic deletion measured by FISH', 'e2': 'poor clinical outcome ', 'relation': ' is a strong independent predictor of ', 'condition': 'after radical prostatectomy'}]"
308,P193P5,"In summary, the results of our study support the prognostic value of PTEN deletion in prostate cancer, which can be further improved in combination with 16p13.3 gain status, suggesting that these genomic alterations may cooperatively contribute to prostate cancer progression. DNA copy number analysis of PTEN and 16p13.3 could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low-grade and intermediate-grade prostate cancer.","[{'e1': 'the results of our study', 'e2': 'prognostic value of PTEN deletion ', 'relation': ' support the ', 'condition': 'in prostate cancer'}]"
309,P194P3,"Baseline mean age, PSA, and GPS score for the cohort were 61.1 years, 8 ng/dL, and 32.8. PTEN loss was noted in 38% of patients by fluorescence in situ hybridization and 25% by immunohistochemistry. The concordance between fluorescence in situ hybridization and immunohistochemistry for PTEN loss was 66%. In univariable analysis, loss of PTEN by fluorescence in situ hybridization or immunohistochemistry was associated with BCR and CR. However, after adjusting for GPS results, PTEN loss was not a significant predictor for CR or BCR. The GPS result remained strongly associated with CR and BCR after adjusting for PTEN status. PTEN status and GPS results only weakly correlated. GPS was widely distributed regardless of PTEN status, indicating the biological heterogeneity of PCa even in PTEN-deficient cases.","[{'e1': 'PTEN loss ', 'e2': '38% of patients ', 'relation': 'was noted in ', 'condition': 'by fluorescence in situ hybridization '}, {'e1': 'PTEN loss ', 'e2': '25% of patients ', 'relation': 'was noted in ', 'condition': 'by immunohistochemistry'}, {'e1': ' loss of PTEN by fluorescence in situ hybridization or immunohistochemistry ', 'e2': 'BCR ', 'relation': 'was associated with ', 'condition': ' In univariable analysis'}, {'e1': ' loss of PTEN by fluorescence in situ hybridization or immunohistochemistry ', 'e2': 'CR', 'relation': 'was associated with ', 'condition': ' In univariable analysis'}, {'e1': 'The GPS result ', 'e2': 'CR ', 'relation': 'remained strongly associated with ', 'condition': 'after adjusting for PTEN status'}, {'e1': 'The GPS result ', 'e2': 'BCR ', 'relation': 'remained strongly associated with ', 'condition': 'after adjusting for PTEN status'}]"
310,P194P4,"GPS is a significant predictor of aggressive PCa, independent of PTEN status. After adjustment for GPS results, PTEN was not independently associated with recurrence for PCa.","[{'e1': 'GPS ', 'e2': 'aggressive PCa ', 'relation': 'is a significant predictor of ', 'condition': 'independent of PTEN status'}, {'e1': ' PTEN ', 'e2': 'recurrence for PCa.', 'relation': 'was not independently associated with ', 'condition': 'After adjustment for GPS results'}]"
311,P194P5,"With increased understanding of molecular pathways of prostate cancer development and progression, several biomarkers for disease aggressiveness have been identified. PTEN, a tumor suppressor gene located on chromosome 10, has been identified as one such biomarker. PTEN expression loss has been noted in 10%-34% of PCa cases and is linked to higher Gleason grade group, advanced tumor stage, and lymph node metastases. Another such biomarker assay, Genomic Prostate Score, has been clinically validated as a predictor of adverse pathology and recurrence noted after radical prostatectomy for clinically localized PCa.","[{'e1': 'Genomic Prostate Score ', 'e2': 'a predictor of adverse pathology and recurrence ', 'relation': 'has been clinically validated as ', 'condition': 'after radical prostatectomy for clinically localized PCa.'}]"
312,P194P8,"The 17-gene GPS assay can significantly predict biochemical recurrence and clinical recurrence after radical prostatectomy independent of PTEN status in men with clinically localized PCa. The GPS assay can risk stratify within PTEN categories and it can help identify patients with PTEN deletion with favorable outcomes, and patients with intact PTEN with unfavorable outcomes.","[{'e1': 'The 17-gene GPS assay ', 'e2': 'biochemical recurrence ', 'relation': 'can significantly predict ', 'condition': 'after radical prostatectomy independent of PTEN status in men with clinically localized PCa '}, {'e1': 'The 17-gene GPS assay ', 'e2': 'clinical recurrence ', 'relation': 'can significantly predict ', 'condition': 'after radical prostatectomy independent of PTEN status in men with clinically localized PCa '}]"
313,P195P6,"In this study, we show that ANO7, a gene specifically expressed in the prostate, is a promising biomarker to predict PrCa aggressiveness. We identified two pathogenic variants that could possibly be utilized in genetic testing of PrCa patients. The stop-gain variant rs148609049 in exon 1 contributes to decreased survival time. The splice site/missense variant rs77559646 in exon 4 increases the risk of PrCa and is also associated with aggressive PrCa. The same variant is an eQTL for ANO7, and high mRNA levels of ANO7 strongly correlate with poor survival. ANO7 gene expression is highly elevated in PrCa tumors versus normal prostate tissue, and high expression strongly increases the PrCa patient mortality rate. These findings should spur further research to elucidate the regulatory networks of ANO7.","[{'e1': 'The stop-gain variant rs148609049 ', 'e2': 'decreased survival time', 'relation': 'contributes to ', 'condition': ' in exon 1 '}, {'e1': 'The splice site/missense variant rs77559646', 'e2': 'the risk of PrCa ', 'relation': ' increases ', 'condition': ' in exon 4'}, {'e1': 'The splice site/missense variant rs77559646', 'e2': 'aggressive PrCa', 'relation': 'is also associated with ', 'condition': ' in exon 4'}]"
314,P196P3,"By NCCN subclassification, 33 (27.3%) and 87 (71.9%) of men were classified as having favorable and unfavorable IR-PCa, respectively (1 case unclassifiable). GC scores were high in 3 favorable IR-PCa and low in 60 unfavorable IR-PCa. Higher GC scores, but not NCCN risk subgroups, were associated with biochemical relapse (hazard ratio, 1.36; 95% confidence interval, 1.09-1.71 per 10% increase; P = .007) and metastasis (hazard ratio, 2.05; 95% confidence interval, 1.24-4.24; P = .004). GC predicted biochemical failure at 5 years (area under the curve, 0.78; 95% confidence interval, 0.59-0.91), and the combinatorial NCCN + GC model significantly outperformed the NCCN alone model for predicting early-onset metastasis (area under the curve for 5-year metastasis of 0.89 vs 0.86 [GC alone] vs 0.54 [NCCN alone]).","[{'e1': ' GC ', 'e2': ' biochemical failure ', 'relation': 'predicted', 'condition': 'at 5 years'}]"
315,P196P5,"Image guided radiation therapy (IGRT) represents a primary treatment modality for localized prostate cancer. Prospective evidence supports combination androgen deprivation therapy (ADT) and IGRT to both improve local control (ie, radiosensitization) and target occult metastases, reducing the disease-specific mortality in high-risk prostate cancer. However, the benefit of systemic intensification is debatable for intermediate-risk prostate cancer (IR-PCa), especially when treated with dose-escalated IGRT (DE-IGRT). The National Comprehensive Cancer Network (NCCN) now endorses including additional factors to subclassify an unfavorable IR-PCa subgroup that is at higher risk of metastatic relapse and prostate cancer-specific mortality and therefore more likely to benefit from combined modality treatments such as ADT with radiation therapy (RT).","[{'e1': 'combination androgen deprivation therapy (ADT) and IGRT ', 'e2': 'the disease-specific mortality ', 'relation': 'reduces', 'condition': 'in high-risk prostate cancer'}]"
316,P196P7,"Here, we evaluate the validity of the 22-gene GC test performed on diagnostic biopsies, accounting for clinicopathologic NCCN risk grouping, for predicting biochemical and metastatic relapse in a cohort of IR-PCa treated with single-modality DE-IGRT at a tertiary cancer center. Of note, there has been only 1 prior study reporting on the utility of a biopsy-derived GC score; it focused on a mixed cohort of intermediate- and high-risk PCa treated with combined ADT and RT. We show that the GC score outperforms the NCCN criteria in distinguishing patients with IR-PCa with favorable outcomes after DE-IGRT without ADT from those who are at risk of metastatic relapse. The GC test may thus be useful for personalizing treatment strategies in IR-PCa, providing actionable information to identify men who should receive combination ADT and DE-IGRT.","[{'e1': ' GC score ', 'e2': 'the NCCN criteria ', 'relation': 'outperforms ', 'condition': 'in distinguishing patients with IR-PCa with favorable outcomes after DE-IGRT without ADT from those who are at risk of metastatic relapse'}, {'e1': 'The GC test ', 'e2': 'personalizing treatment strategies ', 'relation': 'may thus be useful for ', 'condition': 'in IR-PCa'}]"
317,P197P1,"The level of copy number alteration, termed CNA burden, in the tumor genome is associated with recurrence of primary prostate cancer. Whether CNA burden is associated with prostate cancer survival or outcomes in other cancers is unknown. We analyzed the CNA landscape of conservatively treated prostate cancer in a biopsy and transurethral resection cohort, reflecting an increasingly common treatment approach. We find that CNA burden is prognostic for cancer-specific death, independent of standard clinical prognosticators. More broadly, we find CNA burden is significantly associated with disease-free and overall survival in primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in TCGA cohorts. To assess clinical applicability, we validated these findings in an independent pan-cancer cohort of patients whose tumors were sequenced using a clinically certified next generation sequencing assay, where prognostic value varied based on cancer type. This prognostic association was affected by incorporating tumor purity in some cohorts. Overall, CNA burden of primary and metastatic tumors is a prognostic factor, potentially modulated by sample purity and measurable by current clinical sequencing.","[{'e1': 'The level of copy number alteration, termed CNA burden,', 'e2': 'recurrence of primary prostate cancer', 'relation': ' is associated with ', 'condition': 'in the tumor genome'}, {'e1': 'CNA burden ', 'e2': ' disease-free and overall survival ', 'relation': 'is significantly associated with', 'condition': 'in primary breast cancer in TCGA cohorts'}, {'e1': 'CNA burden ', 'e2': ' disease-free and overall survival ', 'relation': 'is significantly associated with', 'condition': 'in endometrial cancer in TCGA cohorts'}, {'e1': 'CNA burden ', 'e2': ' disease-free and overall survival ', 'relation': 'is significantly associated with', 'condition': 'in renal clear cell cancer in TCGA cohorts'}, {'e1': 'CNA burden ', 'e2': ' disease-free and overall survival ', 'relation': 'is significantly associated with', 'condition': 'in thyroid cancer in TCGA cohorts'}, {'e1': 'CNA burden ', 'e2': ' disease-free and overall survival ', 'relation': 'is significantly associated with', 'condition': 'in colorectal cancer in TCGA cohorts'}]"
318,P197P3,"The CNA burden of a tumor is the degree to which a tumor’s genome is altered as a percentage of genome length and represents a fundamental measure of genome copy number alteration level. As such, tumor CNA burden, rather than individual CNAs, may be associated with cancer outcomes. While tumor mutational burden predicts response to immunotherapy across multiple cancer types, tumor CNA burden may be prognostic for outcomes such as recurrence and survival. Indeed, we and others have previously found CNA burden and genome-wide CNA patterns to be associated with biochemical recurrence and metastasis in primary prostate cancer, the most common cancer in men, across multiple cohorts. This prognostic significance of tumor CNA burden extends to low and intermediate risk prostate cancer and has the potential to better stratify risk in patients who are considering conservative treatment approaches such as active surveillance to reduce overtreatment.","[{'e1': ' CNA burden', 'e2': 'biochemical recurrence ', 'relation': 'are associated with ', 'condition': 'in primary prostate cancer'}, {'e1': ' genome-wide CNA patterns ', 'e2': 'biochemical recurrence ', 'relation': 'are associated with ', 'condition': 'in primary prostate cancer'}, {'e1': ' CNA burden', 'e2': 'metastasis ', 'relation': 'are associated with ', 'condition': 'in primary prostate cancer'}, {'e1': ' genome-wide CNA patterns ', 'e2': 'metastasis ', 'relation': 'are associated with ', 'condition': 'in primary prostate cancer'}]"
319,P197P5,"To address these questions, we first examine the genomic CNA landscape of conservatively treated prostate cancer in more than a hundred diagnostic biopsy and resection specimens from a conservatively treated cohort; this cohort consisted of patients with localized prostate cancer who were not treated with surgery or radiation within six months of diagnosis. We demonstrate that tumor CNA burden is associated with cancer-specific death, independent of standard clinical predictors. To explore the prognostic significance of tumor CNA burden more broadly in other cancer types, we find that tumor CNA burden is also associated with disease-free and overall survival in TCGA cohorts of primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in addition to prostate cancer, with the degree of association varying in some cancer types. We then establish the clinical feasibility of measuring tumor CNA burden using the FDA-cleared MSK-IMPACT clinical next generation sequencing assay and confirm that tumor CNA burden is associated with overall and disease-specific survival in both primary and metastatic tumors across cancer types. In all, we demonstrate that tumor CNA burden is a prognostic factor associated with cancer recurrence and death in multiple cancer types, including in conservatively treated prostate cancer which would benefit from increased risk stratification.","[{'e1': 'tumor CNA burden ', 'e2': 'cancer-specific death', 'relation': 'is associated with ', 'condition': 'independent of standard clinical predictors'}, {'e1': 'CNA burden ', 'e2': 'disease-free and overall survival ', 'relation': 'is also associated with ', 'condition': 'in TCGA cohorts of primary breast cancer'}, {'e1': 'CNA burden ', 'e2': 'disease-free and overall survival ', 'relation': 'is also associated with ', 'condition': 'in TCGA cohorts of endometrial cancer'}, {'e1': 'CNA burden ', 'e2': 'disease-free and overall survival ', 'relation': 'is also associated with ', 'condition': 'in TCGA cohorts of renal clear cell cancer'}, {'e1': 'CNA burden ', 'e2': 'disease-free and overall survival ', 'relation': 'is also associated with ', 'condition': 'in TCGA cohorts of thyroid cancer'}, {'e1': 'CNA burden ', 'e2': 'disease-free and overall survival ', 'relation': 'is also associated with ', 'condition': 'in TCGA cohorts of colorectal cancer '}, {'e1': 'CNA burden ', 'e2': 'disease-free and overall survival ', 'relation': 'is also associated with ', 'condition': 'in prostate cancer'}, {'e1': ' tumor CNA burden ', 'e2': 'overall and disease-specific survival ', 'relation': 'is associated with ', 'condition': 'in primary tumors across cancer types'}, {'e1': ' tumor CNA burden ', 'e2': 'overall and disease-specific survival ', 'relation': 'is associated with ', 'condition': 'in metastatic tumors across cancer types'}, {'e1': ' tumor CNA burden ', 'e2': 'cancer recurrence ', 'relation': 'is a prognostic factor associated with ', 'condition': 'in multiple cancer types'}, {'e1': ' tumor CNA burden ', 'e2': 'death ', 'relation': 'is a prognostic factor associated with ', 'condition': 'in multiple cancer types'}]"
320,P197P6,"The prognostic significance of tumor CNA burden raises intriguing questions regarding the underlying biology. Tumor CNA burden may be a simple measure that correlates with the extent of oncogenic driver alterations. Yet, we show that tumor CNA burden retains its prognostic significance after adjustment for a number of known oncogenic alterations in primary prostate cancer, including PTEN loss associated with increased tumor CNA burden. In metastatic tumors, combining tumor CNA burden with TP53 or RB1 loss in multivariable analyses renders both slightly below conventional significance thresholds, raising the possibility of biological interplay between these genes, particularly TP53, and subsequent copy number alteration that develops during tumor evolution. Further, the prognostic associations of tumor CNA burden are independent of tumor ploidy, which suggests that tumor CNA burden may not simply reflect aneuploidy, defined as abnormal DNA content. It is also possible that tumor CNA burden captures prognostic information about currently unidentified driver alterations and/or the rate of ongoing CNA within a tumor that may generate additional driver alterations, including those reflecting intratumoral heterogeneity, thereby affecting outcome. Ongoing work by others has begun to develop genomic methods for identifying mechanisms of somatic CNA and identify prognostic CNA signatures and the mechanisms underlying the component CNA. Ultimately, the biology underlying the significant association of tumor CNA burden with multiple cancer outcomes will be a fruitful area for future investigation.","[{'e1': 'tumor CNA burden ', 'e2': 'prognostic significance ', 'relation': 'retains its ', 'condition': 'after adjustment for a number of known oncogenic alterations in primary prostate cancer'}]"
321,P198P3,"Interplay of HOXB13 (G84E) and CIP2A (R229Q) variants results in the highest observed inherited prostate cancer risk. In addition, this synergism indicates a significant association of HOXB13 T and CIP2A T dual carriers with elevated risk for high Gleason score and worse prostate cancer-specific life expectancy, and it is linked with high PSA at diagnosis. Furthermore, combined high expression of HOXB13-CIP2A correlates with earlier biochemical recurrence. Finally, functional experiments showed that ectopic expression of variants stimulates prostate cancer cell growth and migration. In addition, strong chromatin binding of HOXB13 at the CIP2A locus was observed, and HOXB13 was shown to functionally promote CIP2A transcription. The study is limited to retrospective Nordic cohorts.","[{'e1': 'HOXB13 T and CIP2A T dual carriers ', 'e2': 'high PSA ', 'relation': 'are linked with ', 'condition': 'at diagnosis'}]"
322,P198P6,"One of the strongest prostate cancer risk predictors is the rare recurrent and highly penetrant missense mutation rs138213197/G84E in HOXB13, which codes a homeobox transcription factor that is important in prostate development. There are few additional HOXB13 variants identified in U.S. Caucasians. However, the G84E is a Finnish founder mutation and was recently found to be linked to androgen receptor cistrome reprogramming through cooperating with the pioneer factor FOXA1 in human prostate tumorigenesis. Sharing common haplotype in mutation carriers suggested a founder effect, which was estimated to occur in 1792 in Finland. It is present in 8.4% of Finnish familial prostate cancer cases and represents significantly increased prostate cancer risk also in unselected cases. In unselected prostate cancer cases, the G84E variant was also associated with a considerable risk of prostate cancer in Swedish and UK populations. G84E mutation has been connected with early-onset, familial cases worldwide and explains partly the hereditary component of prostate cancer. Although overexpression of HOXB13 has been linked to several prognostic predictors of prostate cancer and prostate tumorigenesis in men, the associations of G84E with prostate cancer clinical outcomes are not fully known.","[{'e1': ' the G84E ', 'e2': 'androgen receptor cistrome reprogramming ', 'relation': 'is found to be linked to ', 'condition': 'through cooperating with the pioneer factor FOXA1 in human prostate tumorigenesis'}, {'e1': ' the G84E variant ', 'e2': 'a considerable risk of prostate cancer in Swedish and UK populations', 'relation': 'was also associated with ', 'condition': 'In unselected prostate cancer cases'}, {'e1': 'overexpression of HOXB13 ', 'e2': 'several prognostic predictors of prostate cancer ', 'relation': 'has been linked to ', 'condition': 'in men'}, {'e1': 'overexpression of HOXB13 ', 'e2': 'several prognostic predictors of prostate tumorigenesis ', 'relation': 'has been linked to ', 'condition': 'in men'}]"
323,P198P7,"Protein Phosphatase 2A has recently emerged as a potential prostate cancer tumor suppressor. Tumor-suppressor activity of PP2A is inhibited in many cancers by overexpression of endogenous inhibitor proteins, such as SET and CIP2A. Importantly, expression of SET and CIP2A is associated with high Gleason scores and the presence of metastatic disease. CIP2A protein expression is increased in a variety of cancers, including prostate cancer, where it has been associated with castration-resistant prostate cancer. Recently, depletion of CIP2A in CRPC cell lines was shown to sensitize the cells to therapeutic agents. However, even though CIP2A can be considered functionally as a cancer driver protein, genetic evidence for CIP2A mutations in human cancers is very rare. The only genetic study to date of CIP2A in human cancer found that it exerted a synergetic effect with the exonic missense mutation rs2278911, C/T, exon 6, p. R229Q, on the risk of hepatocellular carcinoma in hepatitis B and C virus infection in a Han Chinese population. The high prevalence of C carriers, together with observation that the allele is not associated with hepatocellular carcinoma risk but only has a role in the context of hepatitis infection, suggests that the CIP2A rs2278911 variant might constitute a cooperating oncogene. However, neither the prevalence of rs2278911 in other populations or disease groups, nor the interaction with other genes, nor the potential functional role of this mutation has been studied thus far.","[{'e1': 'Tumor-suppressor activity of PP2A ', 'e2': 'many cancers ', 'relation': 'is inhibited in ', 'condition': 'by overexpression of endogenous inhibitor proteins, such as SET and CIP2A'}]"
324,P19P2,"The heterogeneous disease outcomes of newly diagnosed prostate cancer demand effective prognostic markers to separate aggressive from indolent disease. Genomic alterations, such as chromosome rearrangements that involve ETS transcription factor genes, deletions of PTEN and RB1, and gene amplifications of AR and MYC, are recognized as recurrent events in prostate cancer. The prognostic potential of these and other molecular alterations has yet to be established but could provide important information for guiding treatment recommendations. The most common gene rearrangement in prostate cancer, TMPRSS2:ERG fusion, was determined to be associated with adverse tumor behavior in several studies but not in others. PTEN deletion alone also correlates with more advanced disease at time of surgery and earlier biochemical recurrence (BcR) in several reports. The interaction among different genomic aberrations is also being explored. Reid et al found that PTEN deletion in the absence of ERG/ETV1 gene rearrangements correlated with worse cancer-specific survival.","[{'e1': 'Genomic alterations ', 'e2': ' recurrent events ', 'relation': 'are recognized as', 'condition': 'in prostate cancer'}, {'e1': 'The most common gene rearrangement,TMPRSS2:ERG fusion', 'e2': 'adverse tumor behavior ', 'relation': 'was determined to be associated with ', 'condition': 'in prostate cancer'}, {'e1': 'The most common gene rearrangement in prostate cancer,TMPRSS2:ERG fusion', 'e2': 'adverse tumor behavior ', 'relation': 'was determined to be associated with ', 'condition': 'in several studies'}, {'e1': 'PTEN deletion alone', 'e2': 'more advanced disease at time of surgery ', 'relation': ' also correlates with ', 'condition': 'in several reports'}, {'e1': 'PTEN deletion alone', 'e2': 'earlier biochemical recurrence (BcR) ', 'relation': ' also correlates with ', 'condition': 'in several reports'}, {'e1': 'PTEN deletion ', 'e2': 'worse cancer-specific survival.', 'relation': ' correlated with ', 'condition': 'in the absence of ERG/ETV1 gene rearrangements'}]"
325,P19P3,"We have previously reported that a three-marker fluorescent in situ hybridization (FISH) panel, including AR gene amplification, PTEN deletion, and TMPRSS2/ERG rearrangements, detected higher prevalence of aberrations in castration-resistant or metastatic prostate cancers than in primary prostate tumors. In the current study, we evaluated the prognostic significance of this three-marker FISH panel in a retrospective cohort of primary prostate cancer samples obtained at the time of radical prostatectomy. Abnormalities detected by the panel were correlated with disease stage at the time of radical prostatectomy and for associations with BcR after initial treatment.","[{'e1': 'three-marker fluorescent in situ hybridization (FISH) panel', 'e2': 'aberrations ', 'relation': ' detected higher prevalence of ', 'condition': 'in castration-resistant or metastatic prostate cancers than in primary prostate tumors'}, {'e1': 'Abnormalities detected by the panel ', 'e2': 'disease stage at the time of radical prostatectomy and for associations with BcR ', 'relation': 'were correlated with ', 'condition': 'after initial treatment.'}]"
326,P19P4,"In summary, the three-marker FISH panel for assessing PTEN, TMPRSS2/ERG, and AR abnormalities revealed prognostic utility in a retrospective cohort and identified genomic aberrations associated with advanced disease state and early BcR in localized prostate cancer. Results of an independent cohort support these findings. As such, application of this FISH panel for clinical testing has the merit to identify high-risk patients with prostate cancer prone to early relapse and may help physicians with management decisions regarding whether to subject patients to aggressive therapy or active surveillance.","[{'e1': 'the three-marker FISH panel for assessing PTEN, TMPRSS2/ERG, and AR abnormalities ', 'e2': 'advanced disease state ', 'relation': 'identified genomic aberrations associated with ', 'condition': 'in localized prostate cancer'}, {'e1': 'the three-marker FISH panel for assessing PTEN, TMPRSS2/ERG, and AR abnormalities ', 'e2': 'early BcR ', 'relation': 'identified genomic aberrations associated with ', 'condition': 'in localized prostate cancer'}]"
327,P200P12,"The potential application of DNA methylation in the diagnosis and prognosis of prostate cancer has been widely investigated in the past decade. Most of the accumulated evidences are obtained from studies which focus on a small set of genes, including GSTP1, APC, RUNX3, PITX2, RASSF1A, TGFB2, RARB, HOX genes, and others. For example, promoter methylation in APC and HOXD3 was identified as a biomarker for prostate cancer progression. In the past years, with large-scale epigenome-wide DNA methylation profiling data becoming available, researchers in biomedical communities have been looking for biomarker panels of multiple CpG sites or genes, which are expected to be more predictive, compared with a single-gene signature, for the interested clinical features of cancer patients. In several publications, the authors firstly scanned all the CpG sites of a high-throughput methylation platform to identify the top predictive ones for the interested classification of tumors or the related clinical items. Then, an integrated prediction signature was derived from the previously selected features via the multivariate analysis and/or multiregression analysis. However, such a supervised or semisupervised method often suffers from the problem of overfitting. That is, the robustness of the established prediction signature cannot be guaranteed. In our study, the epigenetically silenced tumor suppressor genes are identified without using the progression features of tumors. So, it is no wonder that the prediction strength of the methylation profiling and expression profiling, especially for Gleason score, is observed in not only the TCGA data but also those two external datasets. It is also logical that the performance of the expression profiling is generally better than that of the methylation profiling. The reason is that DNA methylation of epigenetically silenced tumor suppressor genes takes part in tumor progression via silencing genes, and the expression level of a gene is simultaneously regulated by other factors, such as miRNAs, beyond the promoter methylation status.","[{'e1': 'promoter methylation ', 'e2': 'a biomarker ', 'relation': 'was identified as ', 'condition': 'for prostate cancer progression'}, {'e1': 'promoter methylation ', 'e2': 'a biomarker for prostate cancer progression', 'relation': 'was identified as ', 'condition': 'in APC and HOXD3'}, {'e1': 'DNA methylation of epigenetically silenced tumor suppressor genes ', 'e2': 'tumor progression ', 'relation': 'takes part in ', 'condition': 'via silencing genes'}]"
328,P200P4,We propose a novel method for pinpointing candidate epigenetically silenced tumor suppressor genes in prostate cancer. The expression profiling of the identified genes demonstrates significant prediction strength for tumor progression.,"[{'e1': 'The expression profiling of the identified genes', 'e2': 'significant prediction strength ', 'relation': ' demonstrates ', 'condition': 'for tumor progression.'}]"
329,P200P7,"DNA methylation is a process by which methyl groups are added to a DNA molecule, classically, at cytosine residues. DNA methylation, when located in the promoter of a gene, typically acts to repress gene transcription. In humans, around 60% to 70% of genes have a CpG island in their promoter region, and most of these CpG islands remain unmethylated independently of the transcriptional activity of the gene, in both differentiated and undifferentiated cell types. Cancerous cells usually demonstrate abnormally hypermethylated promoter CpG islands in hundreds of genes. The resulting transcriptional silencing can be inherited by daughter cells following cell division. In prostate tumors, recurrent methylation-mediated epigenetic silencing events have been observed on many cancer-related genes, such as those involved in DNA damage repair, cell-cycle control, apoptosis, and cancerous cell invasion to distant sites.","[{'e1': ' CpG islands ', 'e2': 'unmethylated ', 'relation': 'remain ', 'condition': 'independently of the transcriptional activity of the gene, in both differentiated and undifferentiated cell types'}, {'e1': 'Cancerous cells', 'e2': 'abnormally hypermethylated promoter CpG islands', 'relation': ' usually demonstrate ', 'condition': ' in hundreds of genes'}]"
330,P200P9,"Previous genetics research shows that, although the mutant genotypes of some driver genes may have quite high frequencies or prevalence in a cancer type, no gene is genetically altered in all tumor samples of that cancer. This indicates that the selective advantage of cancer cells is never consistently contributed by a “necessary” driver mutation or driver gene. Based on this viewpoint, it may be not too bold to assume that, for any major cancer types including prostate adenocarcinoma, the promoter methylation in an epigenetically silenced tumor suppressor gene may contribute to carcinogenesis as a driving force but is not a “must” for tumor initiation and progression. In this regard, the primary step for the identification of such a gene is to reveal the stratification of promoter methylation levels within a sample cohort rather than detecting those genes with significant difference between normal tissue and tumor samples.","[{'e1': ' the promoter methylation in an epigenetically silenced tumor suppressor gene ', 'e2': 'carcinogenesis as a driving force', 'relation': 'may contribute to ', 'condition': ' for any major cancer types including prostate adenocarcinoma'}]"
331,P20P2,"Radical prostatectomy (RP) specimens (± disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth.","[{'e1': 'Radical prostatectomy (RP) specimens ', 'e2': 'self-renewal', 'relation': 'were analyzed by qRT-PCR to quantify expression of genes associated with ', 'condition': ' in prior studies'}, {'e1': 'Radical prostatectomy (RP) specimens ', 'e2': 'drug resistance', 'relation': 'were analyzed by qRT-PCR to quantify expression of genes associated with ', 'condition': ' in prior studies'}, {'e1': 'Radical prostatectomy (RP) specimens ', 'e2': ' tumorigenicity', 'relation': 'were analyzed by qRT-PCR to quantify expression of genes associated with ', 'condition': ' in prior studies'}]"
332,P20P3,"Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth.","[{'e1': 'low AXIN2 ', 'e2': 'more aggressive PCa ', 'relation': 'was independently associated with ', 'condition': ' after RP'}, {'e1': 'low AXIN2 ', 'e2': 'biochemical recurrence', 'relation': 'was independently associated with ', 'condition': ' after RP'}, {'e1': 'low AXIN2 ', 'e2': 'metastasis-free survival', 'relation': 'was independently associated with ', 'condition': ' after RP'}]"
333,P20P4,"Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies.","[{'e1': 'Low AXIN2 expression ', 'e2': 'PCa recurrence ', 'relation': 'was associated with ', 'condition': 'after RP'}, {'e1': ' expression levels ', 'e2': 'invasiveness', 'relation': 'significantly impacted ', 'condition': 'in PCa cells '}, {'e1': ' expression levels ', 'e2': 'proliferation', 'relation': 'significantly impacted ', 'condition': 'in PCa cells '}, {'e1': ' expression levels ', 'e2': ' tumor growth', 'relation': 'significantly impacted ', 'condition': 'in PCa cells '}]"
334,P20P6,"Molecular markers to help stratify PCa risk have been proposed. Targets from blood (KLK2-KLK3 SNP rs2735839, 17p12 SNP rs4054823) and primary tissue (immunohistochemistry: p53, Ki67, PTEN loss; fluorescent in situ hybridization: MYC amplification, TMPRSS2-ERG chromosome fusion, PTEN deletion; RNA: cell cycle progression score, miRNA predictor, high grade signatures) have been examined. A few of these have been utilized after RP to predict recurrence and have demonstrated promise. In general, however, integration of molecular characterization of PCa into clinical decision-making has been challenging and may reflect the need for genes that play a more integral role in the biology of PCa tumor renewal and progression. One recent example of this approach in the advanced disease setting was the report that expression levels of a truncated variant of androgen receptor (ARV7) was associated with resistance to AR inhibition in metastatic PCa.","[{'e1': 'A few of these Molecular markers', 'e2': 'recurrence ', 'relation': 'have been utilized to predict ', 'condition': 'after RP'}, {'e1': 'integration of molecular characterization of PCa into clinical decision-making has been challenging ', 'e2': ' genes that play a more integral role', 'relation': 'and may reflect the need for', 'condition': ' in the biology of PCa tumor renewal and progression'}, {'e1': 'expression levels of a truncated variant of androgen receptor (ARV7) ', 'e2': 'resistance to AR inhibition ', 'relation': 'was associated with ', 'condition': 'in metastatic PCa.'}]"
335,P20P7,"The past decade has witnessed a renewed interest in tumor heterogeneity, specifically the presence of cancer cell populations marked by a self-renewing “stem-like” gene expression, drug resistance, and high serial tumorigenicity in mice. We and others have isolated cell subpopulations with these cancer stem-like properties from prostate tumors using low attachment growth conditions and cell surface markers. Notably, the same markers used to identify such cells can play a direct functional role in their aggressive phenotype. For example, CD44 is a cell surface marker that mediates the adhesion of PCa cells to bone marrow derived endothelial cells. CD44high cancer cells with a CSC phenotype possess features indicative of epithelial to mesenchymal transition (EMT), a process by which cells gain migratory and invasive properties. Furthermore, some studies in other malignancies suggest an association between the presence of highly tumorigenic drug resistant subpopulations and tumor grade, degree of invasiveness, and survival outcomes in cancer patients.","[{'e1': ' the presence of highly tumorigenic drug resistant subpopulations', 'e2': ' tumor grade', 'relation': 'is associated with', 'condition': 'in cancer patients.'}, {'e1': ' the presence of highly tumorigenic drug resistant subpopulations', 'e2': ' degree of invasiveness', 'relation': 'is associated with', 'condition': 'in cancer patients.'}, {'e1': ' the presence of highly tumorigenic drug resistant subpopulations', 'e2': 'survival outcomes ', 'relation': 'is associated with', 'condition': 'in cancer patients.'}]"
336,P21P10,"Despite these limitations, our findings are particularly intriguing and provide a unique, more individualized approach to managing men receiving SRT post-RP. Indeed, the GC biomarker provides accurate and comprehensive insight regarding tumor aggressiveness in these individuals. Specifically, this biomarker accurately down-staged almost 50% of patients predicted to harbor very aggressive tumors by clinical features. Most importantly, it accurately identifies a group of men with a 33% 5-yr risk of metastases despite SRT who may be excellent candidates for inclusion into clinical trials for novel therapies due to their very high-risk of metastases despite local salvage therapy.","[{'e1': ' a unique, more individualized approach ', 'e2': ' men ', 'relation': 'to managing', 'condition': 'receiving SRT post-RP'}]"
337,P21P7,"Our ability to predict outcomes following salvage radiation (SRT) for recurrent disease after radical prostatectomy (RP) is poor. A prior study evaluated 1540 men treated with SRT at multiple academic centers. The best nomogram predicted 6-yr prostate specific antigen (PSA) control with 69% accuracy. This compares poorly to other prostate cancer (PCa) nomograms, which predict PCa death (a more definitive endpoint) with 80% accuracy or higher at diagnosis, post-RP, or at initial rising PSA post-RP. While intermediate endpoints (eg, rising PSA) are important, assessment of risk factors for hard endpoints such as metastasis are needed.","[{'e1': 'Our ability ', 'e2': 'outcomes following salvage radiation (SRT) for recurrent disease is poor', 'relation': 'to predict', 'condition': 'after radical prostatectomy (RP)'}]"
338,P21P8,"Advancements in genetics and high throughput “omics” coupled with a robust biomarker discovery program have resulted in several commercially available tissue-based molecular markers for PCa prognosis. While these markers have been evaluated in multiple populations, only one has been examined on patients receiving radiation as primary curative therapy and none in men all receiving SRT. Based upon performance in other populations, a promising test is the Decipher genomic classifier (GC). Unlike other tests that examined a limited number of genes in their discovery, GC examined the whole tumor gene expression profile. Thus, GC has the theoretical advantage of capturing the entire tumor biology in one signature. GC was developed among men undergoing RP at the Mayo Clinic to predict metastases using a nested case-control study design. It has subsequently been evaluated in multiple independent populations receiving varying degrees of postoperative radiation, but never in men who all received SRT. Importantly, these prior studies all included men who received adjuvant radiation, some of whom were cured with surgery alone. As such, it is impossible to assess whether GC predicted response to radiation or the likelihood of the surgery being curative, which invariably would also relate to metastases risk. Therefore, it is crucial to assess the ability of GC to identify metastases risk in a more homogenous group of men who all recurred and all received SRT to address whether GC predicts outcomes after SRT.","[{'e1': 'GC ', 'e2': ' capturing the entire tumor biology', 'relation': 'has the theoretical advantage of', 'condition': ' in one signature'}, {'e1': 'GC', 'e2': 'metastases', 'relation': ' was developed to predict ', 'condition': 'among men undergoing RP at the Mayo Clinic'}, {'e1': ' GC ', 'e2': ' outcomes ', 'relation': 'predicts', 'condition': 'after SRT'}]"
339,P21P9,"To test whether GC predicts metastases after SRT, we performed a multi-center study of men undergoing SRT post-RP. Our population included men from two tertiary-care referral centers and a Veterans Affairs (VA) hospital, which contained nearly 50% African-American men. Importantly, no man in this study cohort was included in the GC development. Thus, this study is an independent evaluation of GC’s ability to predict metastases in men undergoing SRT. We hypothesized GC would predict metastases with high accuracy, especially compared with standard clinico-pathologic variables and two clinico-pathologic risk models: the Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) model and the Briganti risk model, which was developed for predicting biochemical recurrence following early SRT. Neither of these clinico-pathologic risk models were initially designed to predict metastasis. The Briganti model, however, represents a recent and relevant risk model for post-SRT patients while CAPRA-S has been externally validated on a European cohort to predict metastasis.","[{'e1': 'this study ', 'e2': ' GC’s ability to predict metastases', 'relation': 'is an independent evaluation of', 'condition': ' in men undergoing SRT'}]"
340,P22P11,"Despite these limitations, our findings are particularly intriguing and provide a unique, more individualized approach to managing men receiving SRT post-RP. Indeed, the GC biomarker provides accurate and comprehensive insight regarding tumor aggressiveness in these individuals. Specifically, this biomarker accurately down-staged almost 50% of patients predicted to harbor very aggressive tumors by clinical features. Most importantly, it accurately identifies a group of men with a 33% 5-yr risk of metastases despite SRT who may be excellent candidates for inclusion into clinical trials for novel therapies due to their very high-risk of metastases despite local salvage therapy.","[{'e1': 'the GC biomarker ', 'e2': 'tumor aggressiveness ', 'relation': 'provides accurate and comprehensive insight regarding ', 'condition': 'in these individuals'}]"
341,P22P3,"Our comparison revealed 21 differentially expressed snoRNAs in the metastatic vs. non-metastatic xenografts. Of those, 12 were represented in clinical databases and were further analyzed. SNORA55 emerged as a predictor of shorter relapse-free survival (results confirmed in two independent databases). SNORA55 was reproducibly detectable in serum samples from PCa patients. SNORA55 silencing in PCa cell lines significantly inhibited cell proliferation and migration. Pathway analysis revealed that SNORA55 expression is significantly associated with growth factor signaling and pro-inflammatory cytokine expression in PCa. Our results demonstrate that SNORA55 up-regulation predicts PCa progression and that silencing this non-coding gene affects PCa cell proliferation and metastatic potential, thus positioning it as both a novel biomarker and therapeutic target.","[{'e1': 'Our comparison', 'e2': '21 differentially expressed snoRNAs ', 'relation': ' revealed ', 'condition': 'in the metastatic vs. non-metastatic xenografts'}, {'e1': 'SNORA55 silencing ', 'e2': 'cell proliferation and migration', 'relation': ' significantly inhibited ', 'condition': 'in PCa cell lines'}, {'e1': ' SNORA55 expression ', 'e2': ' growth factor signaling and pro-inflammatory cytokine expression ', 'relation': 'is significantly associated with', 'condition': 'in PCa'}]"
342,P22P5,"Recent analyses have revealed that most RNA molecules produced in human cells are not translated into proteins. Included among these non-coding transcripts are microRNAs, which have emerged as critical mediators of cancer progression and potentially useful biomarkers in oncology, as well as long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). Many research groups, including ours, have identified numerous PCa-associated lncRNAs. Indeed it has been shown that the PCA3 lncRNA is detectable in biological fluids and discriminates PCa patients vs. healthy subjects, suggesting that the latter two classes of non-coding RNAs may also be useful as biomarkers.","[{'e1': 'most RNA molecules produced ', 'e2': 'proteins', 'relation': 'are not translated into ', 'condition': 'in human cells'}, {'e1': ' microRNAs', 'e2': 'cancer progression and potentially useful biomarkers ', 'relation': 'which have emerged as critical mediators of ', 'condition': 'in oncology'}]"
343,P22P6,"On the contrary, snoRNAs are a poorly investigated class of non-coding RNAs that are encoded by at least 400 distinct genomic regions. They have traditionally been considered “housekeeping” genes, mainly involved in alternative splicing and ribosomal RNA (rRNA) modifications. In light of their presumptive stable expression, some snoRNAs have been selected as reference genes in studies investigating the expression of microRNAs in human neoplasm. However, recent findings have challenged these assumptions, revealing that snoRNAs can migrate to the cytoplasm and modulate a wide range of cellular functions. At the same time, it has become evident that snoRNA expression patterns are deregulated in cancer cells and in serum samples from cancer patients. In addition, some snoRNAs are emerging as critical mediators of cancer progression. For example SNORA42 is often amplified in lung cancer, and its silencing leads to cancer cell apoptosis, thereby impairing in vivo cancer growth. SNORD50A is frequently deleted and acts as a tumor suppressor in breast cancer and PCa. This gene also represents, to date, the only functionally characterized snoRNA in PCa.","[{'e1': ' some snoRNAs ', 'e2': 'reference genes ', 'relation': 'have been selected as ', 'condition': 'in studies investigating the expression of microRNAs in human neoplasm'}]"
344,P22P7,"We have utilized novel patient tumor tissue-derived xenograft models to identify snoRNAs that were differentially expressed in non-metastatic versus metastatic xenografts derived from the primary tumor of one patient. Differentially expressed snoRNAs were then queried in a test cohort of PCa patients to identify their correlation with disease progression and prognosis. These analyses revealed that SNORA55 was reproducibly associated with worse PCa outcome. In addition, we found that SNORA55 is required for PCa proliferation and migration. Taken together our studies support the hypothesis that SNORA55 may be a novel prognostic biomarker, as well as a novel therapeutic target, in PCa.","[{'e1': 'novel patient tumor tissue-derived xenograft models ', 'e2': ' snoRNAs that were differentially expressed ', 'relation': 'to identify', 'condition': 'in non-metastatic versus metastatic xenografts derived from the primary tumor of one patient'}]"
345,P22P8,"The non-coding transcriptome represents a vast and mainly uncharted region of the human genome whose relevance in neoplasms has been overlooked for many years. SnoRNAs are one of the most abundant non-coding RNA classes and some of them show deregulated expression and/or epigenetic alterations in human neoplasms. Notably, snoRNAs are also detectable in biological fluids, a feature that makes them particularly attractive cancer biomarkers. For these reasons, some authors have predicted that snoRNAs will emerge as novel diagnostic and prognostic tools in the near future. We anticipate that our findings, along with similar studies performed on other neoplasms, will pave the way to the discovery of novel clinically relevant biomarkers and therapeutic targets in oncology.","[{'e1': ' SnoRNAs', 'e2': 'most abundant non-coding RNA classes ', 'relation': ' are one of the ', 'condition': ' in human neoplasms'}, {'e1': ' snoRNAs ', 'e2': 'novel diagnostic and prognostic tools ', 'relation': 'will emerge as ', 'condition': 'in the near future'}, {'e1': 'our findings, along with similar studies performed on other neoplasms', 'e2': 'discovery of novel clinically relevant biomarkers and therapeutic targets ', 'relation': ' will pave the way to the ', 'condition': 'in oncology.'}]"
346,P23P5,"Prostate cancer (PCa) is the most common type of cancer in men, with nearly 220,000 new cases expected in 2015 in USA. The widespread use of serum prostate specific antigen (PSA) as a screening tool led to the increased frequency of PCa diagnoses. A subgroup of patients with extremely localized PCa may be potentially over-treated because only a proportion will develop a clinically detectable disease during their lifespan. PCa is extremely heterogeneous, ranging from a chronic indolent illness to an aggressive rapidly fatal malignancy. Beyond the classical prognostic factors of tumor stage (T), PSA level and Gleason score (GS), to date there are no biological prognostic factors able to discriminate between indolent and aggressive tumors. The abovementioned clinical prognostic factors allow clinicians to categorize patients into broad risk groups (low, intermediate and high risk) but they incompletely explain the observed heterogeneity of clinical outcome. Moreover, specific pathological assessments as, for instance, the GS is operator-dependent and inter-observer variability has been reported. Therefore, new prognosticators are needed to improve clinician’s skill in predicting individual likelihood of each PCa to progress and metastasize.","[{'e1': 'Prostate cancer (PCa) ', 'e2': 'cancer ', 'relation': 'is the most common type of ', 'condition': 'in men'}, {'e1': 'new prognosticators ', 'e2': 'clinician’s skill ', 'relation': 'are needed to improve ', 'condition': 'in predicting individual likelihood of each PCa to progress and metastasize.'}]"
347,P23P6,"Advances in sequencing technologies generated a huge amount of data about the mutational events underlying development, progression and treatment response in cancer. Even if the spectrum of genetic alterations in PCa is heterogeneous, these mutations are more frequently reported in the PI3K and MAPK pathways and in p53, RB and c-MYC genes, all known to affect tumorigenesis in a wide spectrum of tumors, while there are other genetic alterations more specifically reported in PCa. The vast majority of PCa harbors ETS rearrangements, generally as TMPRSS-ERG fusion. In addition, PTEN and TP53 tumor suppressor genes are deleted in about 20–40% of PCa while Speckle-Type POZ Protein mutations occur in about 10% of the samples.","[{'e1': 'Advances in sequencing technologies ', 'e2': 'data about the mutational events underlying development, progression and treatment response ', 'relation': 'generated a huge amount of ', 'condition': 'in cancer'}, {'e1': 'mutations', 'e2': 'PI3K ', 'relation': 'are more frequently reported in', 'condition': 'in PCa'}, {'e1': 'mutations', 'e2': 'MAPK pathways', 'relation': 'are more frequently reported in', 'condition': 'in PCa'}, {'e1': 'mutations', 'e2': ' p53 ', 'relation': 'are more frequently reported in', 'condition': 'in PCa'}, {'e1': 'mutations', 'e2': 'RB ', 'relation': 'are more frequently reported in', 'condition': 'in PCa'}, {'e1': 'mutations', 'e2': 'c-MYC genes', 'relation': 'are more frequently reported in', 'condition': 'in PCa'}]"
348,P23P8,"In conclusion, this is one of the first retrospective studies that tested the feasibility of NGS for PCa genetic characterization using FFPE archival material. Although the limited number of patients limits the statistical power of the analyses, the reported results are in agreement with previously published data suggesting a complex mutational pattern in PCa. In addition, our data support the involvement of TP53, MET, FGFR3, CSF1R GVs in PCa, mainly influencing tumor progression or aggressiveness. Some of these GVs, such as CSFR1 SNPs or KIT p.M541L may potentially contribute, if data will be confirmed in larger studies, to customized treatments with targeted therapies.","[{'e1': 'our data ', 'e2': 'TP53, MET, FGFR3, CSF1R GVs ', 'relation': 'support the involvement of ', 'condition': 'in PCa'}]"
349,P24P1,"To develop new methods to distinguish indolent from aggressive prostate cancers (PCa), we utilized comprehensive high-throughput array-based relative methylation (CHARM) assay to identify differentially methylated regions (DMRs) throughout the genome, including both CpG island (CGI) and non-CGI regions in PCa patients based on Gleason grade. Initially, 26 samples, including 8 each of low [Gleason score (GS) 6] and high (GS ‚â•7) grade PCa samples and 10 matched normal prostate tissues, were analyzed as a discovery cohort. We identified 3,567 DMRs between normal and cancer tissues, and 913 DMRs distinguishing low from high-grade cancers. Most of these DMRs were located at CGI shores. The top 5 candidate DMRs from the low vs. high Gleason comparison, including OPCML, ELAVL2, EXT1, IRX5, and FLRT2, were validated by pyrosequencing using the discovery cohort. OPCML and FLRT2 were further validated in an independent cohort consisting of 20 low-Gleason and 33 high-Gleason tissues. We then compared patients with biochemical recurrence (n = 70) vs. those without (n = 86) in a third cohort, and they showed no difference in methylation at these DMR loci. When GS 3+4 cases and GS 4+3 cases were compared, OPCML-DMR methylation showed a trend of lower methylation in the recurrence group (n = 30) than in the no-recurrence group (n = 52). We conclude that whole-genome methylation profiling with CHARM revealed distinct patterns of differential DNA methylation between normal prostate and PCa tissues, as well as between different risk groups of PCa as defined by Gleason scores. A panel of selected DMRs may serve as novel surrogate biomarkers for Gleason score in PCa.","[{'e1': 'comprehensive high-throughput array-based relative methylation (CHARM) assay ', 'e2': 'differentially methylated regions (DMRs) throughout the genome, including both CpG island (CGI) and non-CGI regions ', 'relation': 'to identify ', 'condition': 'in PCa patients based on Gleason grade'}, {'e1': ' A panel of selected DMRs ', 'e2': 'novel surrogate biomarkers for Gleason score ', 'relation': 'may serve as ', 'condition': 'in PCa.'}]"
350,P24P2,"Prostate cancer (PCa) is the most common cancer in men in the US. The natural history and clinical course of PCa is very heterogeneous: some are indolent with little effect on overall lifespan, whereas others can progress to lethal metastatic disease. The test commonly used to screen for PCa is the prostate specific antigen test (PSA); however, many other factors can affect PSA levels and result in high false-positive findings. Furthermore, current therapeutic modalities have complications that may lead to significant morbidity. Therefore, new methods are needed to distinguish indolent cancers from their aggressive counterparts.","[{'e1': 'Prostate cancer (PCa) ', 'e2': ' cancer in men ', 'relation': 'is the most common', 'condition': 'in the US'}]"
351,P24P3,"One promising approach is DNA methylation profiling. Changes in DNA methylation, with accompanied epigenetic gene silencing, appear to be the earliest somatic genomic alterations recognized in human PCa and continue throughout disease progression. Hypermethylation of promoter CpG islands (CGIs) can silence tumor suppressor genes early during tumorigenesis, while significant global hypomethylation arises later in PCa progression. It is likely that different patterns of DNA methylation may distinguish aggressive vs. indolent PCa and predict responses to specific treatments. Earlier studies have shown that promoter hypermethylation of specific genes are associated with PCa progression. The best characterized gene, glutathione S-transferase-p (GSTP1), shows promoter hypermethylation in more than 90% of PCas from numerous independent analyses. Other methylation-mediated gene silencing has been reported in more than 40 genes, including APC, RARβ, and RASSF1A, and the number continues to grow. However, no consistent conclusions can be drawn regarding the predictive value of these methylation markers.","[{'e1': 'Changes in DNA methylation, with accompanied epigenetic gene silencing', 'e2': 'the earliest somatic genomic alterations recognized ', 'relation': 'appear to be ', 'condition': 'in human PCa'}]"
352,P24P4,"In addition, most studies that evaluate global gene methylation focus on the promoter CGI region and leave the regions outside CGIs largely unexplored. However, recent studies have demonstrated that methylation of CpG dinucleotides up to 2 kb away from CGI (the CGI “shores”) can better distinguish different tissues as well as cancer and normal tissues. We applied the comprehensive high-throughput arrays for relative methylation method (CHARM), which is a custom-designed NimbleGen HD2 microarray containing approximately 4.6 million CpG sites across the genome, to thoroughly examine all CpG dinucleotides in the genome. Because CHARM includes all CpGs in the genome, it is a non-biased methylation array that allows the identification of differentially methylated regions (DMRs) located in both CGI and non-CGI regions. We have successfully identified a series of genome-wide DMRs that can stratify normal vs. PCa and low-grade vs. high-grade PCa cases based on the Gleason score.","[{'e1': ' We applied the comprehensive high-throughput arrays for relative methylation method (CHARM) ', 'e2': 'all CpG dinucleotides', 'relation': 'to thoroughly examine ', 'condition': 'in the genome'}, {'e1': ' CHARM ', 'e2': 'differentially methylated regions (DMRs) ', 'relation': ' allows the identification of ', 'condition': 'located in CGI '}, {'e1': ' CHARM ', 'e2': 'differentially methylated regions (DMRs) ', 'relation': ' allows the identification of ', 'condition': 'located in CGI '}]"
353,P25P1,"This study examined whether differential DNA methylation is associated with clinical features of more aggressive disease at diagnosis and prostate cancer recurrence in African American men, who are more likely to die from prostate cancer than other populations. Tumor tissues from 76 African Americans diagnosed with prostate cancer who had radical prostatectomy as their primary treatment were profiled for epigenome-wide DNA methylation levels. Long-term follow-up identified 19 patients with prostate cancer recurrence. Twenty-three CpGs were differentially methylated (FDR q≤0.25, mean methylation difference ≥0.10) in patients with vs. without recurrence, including CpGs in GCK, CDKL2, PRDM13, and ZFR2. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence (five CpGs), regional vs. local pathological stage (two CpGs), and higher vs. lower tumor aggressiveness (one CpG). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness.","[{'e1': 'differential DNA methylation ', 'e2': 'clinical features of more aggressive disease at diagnosis and prostate cancer recurrence ', 'relation': 'is associated with ', 'condition': 'in African American men, who are more likely to die from prostate cancer than other populations'}]"
354,P25P4,"There are few investigations that have examined aberrant DNA methylation in African American PCa patients, and these mainly consist of candidate gene studies. For instance, Tang et al. reported that hypermethylation of RARB was significantly associated with a higher risk of PCa in African American men but not in men of European ancestry. Woodson et al. described hypermethylation of CD44 in tumor tissues from African Americans (43% compared to 25% in European Americans), and found that this was positively correlated with tumor grade. The one publication to date that focused on epigenome-wide DNA methylation in African American PCa patients analyzed only three tumors in this high-risk population. That study found that the promoter regions of several genes, including SNRPN, MST1R, and ABCG5, were hypermethylated in African Americans compared to European Americans.","[{'e1': ' few investigations ', 'e2': 'aberrant DNA methylation ', 'relation': 'that have examined ', 'condition': 'in African American PCa patients'}, {'e1': 'hypermethylation of RARB ', 'e2': 'a higher risk of PCa ', 'relation': 'was significantly associated with ', 'condition': 'in African American men'}]"
355,P26P3,"Prostate cancer is one of the most commonly diagnosed cancers in men. Although the incidence of prostate cancer is lower in Asians than in other ethnic groups, its incidence has risen rapidly and it has become one of the major cancer-related deaths in Asia. Radical prostatectomy (RP) and androgen-deprivation therapy (ADT) are the most common treatment options for localized and advanced prostate cancer, respectively. Despite the initial efficacy of treatment, a subset of patients eventually develops recurrent disease. Thus, there is an urgent need to identify novel biomarkers that can guide patient management.","[{'e1': 'Prostate cancer ', 'e2': ' the major cancer-related deaths ', 'relation': 'has risen rapidly and it has become one of', 'condition': 'in Asia'}]"
356,P26P5,"To our knowledge, this is the first association study using three independent cohorts to assess the influence of SNPs within UCRs on prostate cancer progression and mortality. It should be noted that the homogeneous Taiwanese population in this study may limit the generalization of these findings to other ethnic groups. However, the results are supported by the association of rs8004379 with prostate cancer progression from both localized and advanced patients, as well as the consistent in silico functional findings. This molecular marker might lead to a better patient stratification, and optimize therapeutic interventions in patients with a high risk of recurrence who are more likely to benefit from treatment. Further fine mapping will help to identify the causative variants responsible for the observed associations, and functional studies will also be necessary to elucidate the underlying biological mechanisms.","[{'e1': ' This molecular marker ', 'e2': ' better patient stratification', 'relation': 'might lead to a', 'condition': ' in patients with a high risk of recurrence who are more likely to benefit from treatment'}, {'e1': ' This molecular marker ', 'e2': ' therapeutic interventions', 'relation': 'might optimize', 'condition': ' in patients with a high risk of recurrence who are more likely to benefit from treatment'}]"
357,P27P1,"Limitations of current diagnostic and prognostic tools for prostate cancer (PC) have led to over-diagnosis and over-treatment. Here, we investigate the biomarker potential of the SLC18A2 (VMAT2) gene for PC at three molecular levels. Thus, SLC18A2 promoter methylation was analyzed in 767 malignant and 78 benign radical prostatectomy (RP) samples using methylation-specific qPCR and Illumina 450K methylation microarray data. SLC18A2 transcript levels were assessed in 412 malignant and 45 benign RP samples using RNAseq data. SLC18A2 protein was evaluated by immunohistochemistry in 502 malignant and 305 benign RP samples. Cancer-specificity of molecular changes was tested using Mann-Whitney U tests and/or receiver operating characteristic (ROC) analyses. Log-rank, uni- and multivariate Cox regression tests were used for survival analyses. We found that SLC18A2 promoter hypermethylation was highly cancer-specific (area under the curve (AUC): 0.923–0.976) and associated with biochemical recurrence (BCR) after RP in univariate analyses. SLC18A2 transcript levels were reduced in PC and had independent prognostic value for BCR after RP (multivariate HR 0.13, P < 0.05). Likewise, SLC18A2 protein was down-regulated in PC (AUC 0.898) and had independent prognostic value for BCR (multivariate HR 0.51, P < 0.05). Reduced SLC18A2 protein expression was also associated with poor overall survival in univariate analysis (HR 0.29, P < 0.05). Our results highlight SLC18A2 as a new promising methylation marker candidate for PC diagnosis. Furthermore, SLC18A2 expression (RNA and protein) showed promising prognostic potential beyond routine clinicopathological variables. Thus, novel SLC18A2-based molecular tests could have useful future applications for PC detection and identification of high-risk patients.","[{'e1': 'the biomarker potential ', 'e2': ' SLC18A2 (VMAT2) gene for PC', 'relation': 'of the', 'condition': ' at three molecular levels'}, {'e1': 'SLC18A2 promoter hypermethylation ', 'e2': 'biochemical recurrence (BCR)', 'relation': 'associated with ', 'condition': ' after RP in univariate analyses'}, {'e1': 'SLC18A2 transcript levels ', 'e2': 'PC and had independent prognostic value for BCR ', 'relation': 'were reduced in', 'condition': 'after RP'}, {'e1': 'Reduced SLC18A2 protein expression ', 'e2': 'poor overall survival', 'relation': 'was also associated with ', 'condition': ' in univariate analysis '}]"
358,P27P2,"Prostate cancer is the most frequent male cancer in the developed world. Whereas most prostate cancers are relatively slow growing and tumors localized to the prostate can be cured by radical prostatectomy (RP) or radiation therapy, metastatic prostate cancer is incurable. Thus, early detection and treatment is essential. Many prostate cancers, however, may not cause clinical symptoms within the patient’s lifetime and as treatment is associated with severe side-effects, only men with aggressive prostate cancer should be treated. Prostate cancer is definitively diagnosed by histopathological evaluation of prostate biopsies, but the initial indicator is often increased serum prostate specific antigen (PSA). Serum PSA has relatively high sensitivity, but rather low specificity for prostate cancer. Its use has therefore led to a large increase in prostate cancer diagnoses and treatments. Due to the high prevalence of indolent prostate cancers and lack of accurate prognostic tools to guide treatment decisions, a significant number of men may be over-treated. Novel molecular markers may aid in early detection and in determining the aggressiveness of prostate cancer, but are generally not used in current clinical practice.","[{'e1': 'Serum PSA use ', 'e2': 'a large increase ', 'relation': 'has therefore led to ', 'condition': 'in prostate cancer diagnoses and treatments'}]"
359,P27P3,"Prostate cancer is characterized by aberrant DNA hypermethylation of promoter-associated CpG islands at a large number of genes. A subset of these genes show reduced mRNA expression upon DNA methylation, and hence are potential drivers of cancer development and often considered candidate tumor suppressors. Candidate DNA methylation markers for prostate cancer have been reported to be hypermethylated in 70–100% of prostate cancer samples and are thus highly attractive for diagnostic applications. In addition, a few candidate DNA methylation markers have demonstrated promising prognostic value for prediction of PSA recurrence after RP.","[{'e1': 'Prostate cancer ', 'e2': 'aberrant DNA hypermethylation of promoter-associated CpG islands ', 'relation': 'is characterized by ', 'condition': 'at a large number of genes'}, {'e1': 'Candidate DNA methylation markers for prostate cancer ', 'e2': 'hypermethylated', 'relation': 'have been reported to be ', 'condition': ' in 70–100% of prostate cancer samples'}, {'e1': 'a few candidate DNA methylation markers ', 'e2': ' promising prognostic value for prediction of PSA recurrence ', 'relation': 'have demonstrated', 'condition': 'after RP'}]"
360,P27P4,"The solute carrier family 18 member 2 (SLC18A2) gene encodes the transmembrane protein vesicular monoamine transporter 2 (SLC18A2/VMAT2). SLC18A2 protein localization and function is well characterized in neuronal cells where it facilitates uptake of monoamines into cytoplasmic large dense core and synaptic vesicles. SLC18A2 is highly expressed in monoamine secreting neuroendocrine tumors. In contrast, we previously reported a reduction in SLC18A2 immunoreactivity levels in 506 prostate adenocarcinoma samples when compared to 70 benign prostate tissue samples. In addition, in our previous study, reduced SLC18A2 protein levels had independent prognostic value for PSA recurrence after RP in multivariate Cox regression analysis including standard clinicopathological parameters, but this was not validated in an independent cohort. Notably, our previous results indicated hypermethylation of the SLC18A2 promoter-associated CpG island and reduced SLC18A2 mRNA expression in prostate cancer, but this was based only on small patient sample sets (n < 21).","[{'e1': 'reduced SLC18A2 protein levels ', 'e2': 'PSA recurrence ', 'relation': 'had independent prognostic value for ', 'condition': 'after RP in multivariate Cox regression analysis'}, {'e1': 'hypermethylation of the SLC18A2 promoter ', 'e2': ' CpG island and reduced SLC18A2 mRNA expression ', 'relation': 'associated', 'condition': 'in prostate cancer'}]"
361,P28P1,"Radiation therapy (RT) is one of the mainstay treatments for prostate cancer (PCa). The potentially curative approaches can provide satisfactory results for many patients with non-metastatic PCa; however, a considerable number of individuals may present disease recurrence and die from the disease. Exploiting the rich molecular biology of PCa will provide insights into how the most resistant tumor cells can be eradicated to improve treatment outcomes. Important for this biology-driven individualized treatment is a robust selection procedure. The development of predictive biomarkers for RT efficacy is therefore of utmost importance for a clinically exploitable strategy to achieve tumor-specific radiosensitization. This review highlights the current status and possible opportunities in the modulation of four key processes to enhance radiation response in PCa by targeting the: (1) androgen signaling pathway; (2) hypoxic tumor cells and regions; (3) DNA damage response (DDR) pathway; and (4) abnormal extra-/intracell signaling pathways. In addition, we discuss how and which patients should be selected for biomarker-based clinical trials exploiting and validating these targeted treatment strategies with precision RT to improve cure rates in non-indolent, localized PCa.","[{'e1': ' targeted treatment strategies with precision RT ', 'e2': 'cure rates ', 'relation': 'to improve ', 'condition': 'in non-indolent, localized PCa.'}]"
362,P28P2,"In 2014, it was estimated that over 233,000 men would be diagnosed with prostate cancer (PCa) in North America leading to over 29,480 deaths. The prognosis and treatment of these men is currently determined by a number of different risk classification systems. All of these use combinations of the conventional risk stratifications: TNM staging, pathologic Gleason score (GS), and prostate specific antigen (PSA) level. Treatment options vary from active surveillance for indolent low-risk PCa to different combinations of external beam radiotherapy (RT), brachytherapy, androgen deprivation therapy (ADT), and surgery. A comprehensive review of levels of evidence for the use of different types of treatment technologies, RT dose escalation, and the use of ADT is beyond the scope of this review, and the reader is pointed to several recent reviews in this area.","[{'e1': 'over 233,000 men ', 'e2': ' prostate cancer (PCa) ', 'relation': 'would be diagnosed with', 'condition': 'in North America'}]"
363,P28P3,"Despite the use of clinical prognostic factors and improved technological advances in radiation delivery and surgery, patients with localized PCa are at risk for local failure and occult metastases not appreciated by current radiographic staging prior to treatment. Local recurrence after RT is thought to occur predominantly in regions bearing higher histological tumor burden. Thus, strategies that improve both local control at the tumor site and eradicate occult metastases are required.","[{'e1': 'patients with localized PCa', 'e2': 'local failure ', 'relation': ' are at risk for ', 'condition': 'prior to treatment'}, {'e1': 'patients with localized PCa', 'e2': ' occult metastases not appreciated by current radiographic staging ', 'relation': ' are at risk for ', 'condition': 'prior to treatment'}]"
364,P28P4,"There is a pressing need to develop novel radiosensitizing strategies and agents to specifically target tumor cells to improve treatment outcome. Research exploiting the tumor-specific biology in relation to the normal tissue cells will reveal the Achilles heel of the most resistant tumor cells and regions. In this review we focus on approaches that combine RT with one or more agents to enhance the radiation response specifically for tumor cells. We focus on four important pathways that could influence RT outcome, including the: (1) androgen signaling pathway; (2) hypoxic tumor cells and regions; (3) DNA damage response (DDR) pathway; and (4) abnormal extra-/intracell signaling pathways. In addition, we provide an insight into which patients will benefit from this approach and how to select these patients by clinically feasible biomarkers.","[{'e1': 'approaches that combine RT ', 'e2': 'radiation response ', 'relation': 'with one or more agents to enhance the ', 'condition': 'specifically for tumor cells'}]"
365,P28P7,"The technological advances and the lower costs in genomic medicine should help standardize and validate assays for molecular characterizations. This is determining personalized PCa genomics and reflecting specific patterns of tumor progression. Incorporation of this knowledge into biomarker-based prospective clinical trials will enable us to marry precision RT, novel targeted agents, and biological endpoints in order to improve cure rates in non-indolent PCa.","[{'e1': ' Incorporation of this knowledge into biomarker-based prospective clinical trials will enable us to marry precision RT', 'e2': 'cure rates ', 'relation': ' in order to improve ', 'condition': 'in non-indolent PCa.'}, {'e1': ' Incorporation of this knowledge into biomarker-based prospective clinical trials will enable us to marry novel targeted agents', 'e2': 'cure rates ', 'relation': ' in order to improve ', 'condition': 'in non-indolent PCa.'}, {'e1': ' Incorporation of this knowledge into biomarker-based prospective clinical trials will enable us to marry biological endpoints', 'e2': 'cure rates ', 'relation': ' in order to improve ', 'condition': 'in non-indolent PCa.'}]"
366,P29P1,"Prostate cancer is the second most frequently diagnosed cancer in men worldwide. Current treatments include surgery, androgen ablation and radiation. Introduction of more targeted therapies in prostate cancer, based on a detailed knowledge of the signalling pathways, aims to reduce side effects, leading to better clinical outcomes for the patient. ADAM19 (A Disintegrin And Metalloproteinase 19) is a transmembrane and soluble protein which can regulate cell phenotype through cell adhesion and proteolysis. ADAM19 has been positively associated with numerous diseases, but has not been shown to be a tumor suppressor in the pathogenesis of any human cancers. Our group sought to investigate the role of ADAM19 in human prostate cancer.","[{'e1': 'Prostate cancer', 'e2': 'diagnosed cancer ', 'relation': ' is the second most frequently ', 'condition': 'in men worldwide'}]"
367,P29P10,"Our study provides evidence that elevated ADAM19 expression may serve as a tumor suppressor in human prostate cancer. Using human normal and prostate cancer biopsies, we show that ADAM19 protein levels are elevated in normal prostate and reduced in prostate cancer specimens. Our clinical data from two different cohorts provides compelling results for involvement of ADAM19 in prostate cancer and our in vitro data shows that ADAM19 can regulate prostate cancer cell growth and migration. Intriguingly, it would appear that the effects of ADAM19 may be limited to prostate cancer cells with reduced expression of ADAM19. These data provide for the first time a foundation to further explore the mechanism by which ADAM19 exerts its tumor suppressor effects and raises the possibility that expression of ADAM19 levels in prostate cancer tumors could become a useful biomarker in the disease.","[{'e1': 'elevated ADAM19 expression ', 'e2': 'tumor suppressor ', 'relation': 'may serve as a ', 'condition': 'in human prostate cancer'}, {'e1': ' compelling results', 'e2': ' ADAM19 ', 'relation': ' for involvement of', 'condition': 'in prostate cancer'}, {'e1': ' expression of ADAM19 levels in prostate cancer tumors ', 'e2': 'useful biomarker ', 'relation': 'could become a ', 'condition': 'in the disease.'}]"
368,P29P9,"Based on the emerging evidence of ADAM involvement in human cancer, we were interested to investigate if ADAM19 might play a role in prostate cancer using a combination of clinical cohorts and in vitro analyses. We found that ADAM19 is a tumor suppressor in human prostate cancer patients and that it inhibits prostate cancer cell proliferation and migration in cell culture.","[{'e1': 'ADAM19 ', 'e2': 'prostate cancer cell proliferation and migration ', 'relation': 'inhibits ', 'condition': 'in cell culture.'}]"
369,P30P3,"Recently, exome sequencing has discovered novel somatic mutations of considerable frequencies in PCa, which is a remarkable discovery considering that a recurrent mutation is a rare event in PCa. One of the frequently mutated genes was Mediator complex subunit 12 (MED12) gene located on Xq13.1, which encodes a subunit of a multi-protein complex called Mediator. The mediator plays an essential role in the transcription machinery and is composed of a set of distinct modules. MED12 participates in the formation of the CDK8 kinase module of the mediator complex, thereby engaging in the nuclear transduction of signals from several different oncogenic pathways, and it was suggested that MED12 mutation may indirectly affect p53 or androgen signaling.","[{'e1': 'exome sequencing', 'e2': 'novel somatic mutations of considerable frequencies ', 'relation': ' has discovered ', 'condition': 'in PCa'}]"
370,P30P4,"However, one subsequent study failed to find evidence for a frequent mutation in a Caucasian population, possibly due to the difference in the composition of the study cohort. Thus, in this study, we investigated the mutation status of MED12 in 102 radical prostatectomy specimens from Korean men to explore its relevance in this distinct ethnic group, testing the possibility that MED12 may represent another point of molecular difference between the Caucasian and Asian population.","[{'e1': 'one subsequent study ', 'e2': 'a frequent mutation ', 'relation': 'failed to find evidence for ', 'condition': 'in a Caucasian population'}, {'e1': ' the mutation status of MED12 in 102 radical prostatectomy specimens from Korean men ', 'e2': 'relevance ', 'relation': 'to explore its ', 'condition': 'in this distinct ethnic group'}]"
371,P30P5,"Thus, it appears worthwhile to explore the presence of MED12 mutation in PCa from Korean patients, and we hypothesized that MED12 mutation may constitute one of the molecular alterations that are more frequent in PCa of the Asian population considering that the MED12-mediated pathway may affect androgen receptor signaling, which is heavily dependent on ethnicity. The results of our study are not supportive of this hypothesis, and it remains to be unveiled what molecular mechanism is more actively operating in PCa of Korean and Asian patients than in PCa of Western patients.","[{'e1': 'MED12 mutation ', 'e2': 'molecular alterations that are more frequent ', 'relation': 'may constitute one of the ', 'condition': 'in PCa of the Asian population'}]"
372,P31P2,"Prostate cancer (PCa) is the most common non-cutaneous cancer among men in the United States, and can be successfully treated if it is diagnosed early before metastasizing to bones or other organs. Over 240,000 men are diagnosed with prostate cancer in the US annually, and a majority harbor local or regional disease where the long-term prognosis is excellent. In contrast, the 5-year survival rate is only ~28% for distant-stage prostate cancer that already has metastasis in bones or other organs. Radical prostatectomy (RP), a surgical removal of all of the prostate gland, the seminal vesicles and the vas deferens, is one of the treatment options when the cancer is confined to the prostate. Nearly 40% of the patients undergoing RP present clinic-pathologic features associated with increased risk of clinical metastasis such as rising PSA (Prostate Specific Antigen), high Gleason score, seminal vesicle invasion or lymph node involvement. By and large, these clinical features are used for determining risk group of PCa and there are various classification methods that are adopted by different medical organizations and entities. The great heterogeneity in prognoses of patients undergoing RP requires more effort in optimizing patient management to tailor proper treatments. In this respect, the factors that have enhanced capacity to predict risk of metastasis, and death of PCa following RP are indeed crucial for the successful treatment and clinical outcome of this disease.","[{'e1': 'Over 240,000 men ', 'e2': ' prostate cancer ', 'relation': 'are diagnosed with', 'condition': 'in the US annually'}, {'e1': 'the 5-year survival rate', 'e2': ' distant-stage prostate cancer', 'relation': ' is only ~28% for', 'condition': 'that already has metastasis in bones or other organs'}]"
373,P31P3,"Not only are epigenetic mechanisms, including DNA methylation, essential for normal development by regulating gene transcription involved with cell division or differentiation, but they also control a number of key processes including tumorigenesis. Many studies revealed that, in disease processes such as cancer, abnormal DNA hypermethylation in the promoter regions of genes causes transcriptional silencing. Recent studies show that gene body (genic) methylation also plays an important role in the alteration of gene expression. There is a causal relationship between genic DNA methylation and gene expression, which indicates that methylation at genic regions could be a therapeutic target in cancer. Distal regulatory elements are also subject to epigenetic modification and could be a key feature of the cancer epigenomes.","[{'e1': ' gene body (genic) methylation ', 'e2': ' important role ', 'relation': 'also plays an', 'condition': 'in the alteration of gene expression'}, {'e1': ' methylation at genic regions', 'e2': 'therapeutic target ', 'relation': ' could be a ', 'condition': 'in cancer'}]"
374,P31P4,"Many aspects of the regulatory roles of DNA methylation are not fully understood. For instance, the collaborative roles among distal, gene body and promoter methylation besides their individual role remain unknown. It is worthwhile to put forth efforts in conducting such genome-wide methylation pattern analysis and understanding their impact on gene expression. On this basis, we conducted this study by applying a MBD-seq protocol previously established in our laboratory on a cohort of 32 PCa prostatectomy specimens, as well as 8 normal (N) and 12 tumor-adjacent specimens (ADJ). The grouping of patients were determined by applying widely used risk classification methods, and the final grouping included low risk (L), high risk (H) and very high risk (VH). The result in methylation study was correlated with the RNA-seq data from The Cancer Genome Atlas (TCGA). We sought to investigate the methylation pattern in the four genomic regions based on a gene structure, i.e., 5′-Distal region, TSS, Genic and TES, and to identify genes with differential methylations among tumor and normal samples. We further performed inter-correlation analysis on those identified differential DMRs between TSS region and the other three genomic regions to identify the CDMPs. Next, in order to elucidate the impact of DNA methylation on gene expression we correlated the significant CDMPs with gene expression values obtained from TCGA RNA-seq. IPA analysis on significantly differentially expressed genes in these three groups hinted the involvement of AR/TP53 related signaling network, and this pathway-associated genes were further investigated in a survival analysis. To summarize, we demonstrate DNA methylation in distal and intragenic regions also plays critical roles in prostate tumorigenesis, and may act either positively or negatively with TSS to alter gene regulation in tumors. The identified gene clusters could be potential biomarkers that might be immensely helpful in the management of PCa patients particularly in the process of deciding proper treatment option at the time of RP.","[{'e1': ' The identified gene clusters ', 'e2': 'potential biomarkers ', 'relation': 'could be ', 'condition': ' in the management of PCa patients'}, {'e1': 'The identified gene clusters', 'e2': 'the management of PCa patients ', 'relation': ' might be immensely helpful in ', 'condition': ' at the time of RP.'}]"
375,P31P5,"PCa is the most common cancer among men but could be the least life-threatening if it receives proper treatment. However, the current prevailing clinical screening or testing approach suffers from limitations because of the inability to manage patients particularly with respect to prevent over- or insufficient treatments. Our genome-wide study for the first time provides thousands of differential methylation regions as well as the genes associated with many different collaborative differential methylation patterns for PCa. Furthermore, our work provides insight into how DNA methylation in Distal and Genic regions might play critical roles in contributing to prostate tumorigenesis and henceforth may act either positively or negatively with TSS to alter gene regulation in tumors.","[{'e1': 'DNA methylation ', 'e2': ' prostate tumorigenesis', 'relation': 'might play critical roles in contributing to', 'condition': 'in Distal and Genic regions'}, {'e1': 'DNA methylation ', 'e2': 'gene regulation ', 'relation': ' acts positively or negatively with TSS to alter ', 'condition': 'in tumors.'}]"
376,P32P1,Multi-parametric magnetic resonance imaging (MP-MRI) is currently the most comprehensive work up for non-invasive primary tumor staging of prostate cancer (PCa). Prostate-specific membrane antigen (PSMA)-positron emission tomography-computed tomography (PET/CT) is presented to be a highly promising new technique for N- and M-staging in recurrent PCa patients. The present investigation analyses the potential of 68Ga-PSMA-11-PET/CT to assess the extent of primary prostate cancer by intra-individual comparison to MP-MRI.,"[{'e1': 'Prostate-specific membrane antigen (PSMA)-positron emission tomography-computed tomography (PET/CT) ', 'e2': 'highly promising new technique for N- and M-staging ', 'relation': 'is presented to be a ', 'condition': 'in recurrent PCa patients'}, {'e1': 'the potential of 68Ga-PSMA-11-PET/CT', 'e2': 'primary prostate cancer ', 'relation': ' to assess the extent of ', 'condition': 'by intra-individual comparison to MP-MRI.'}]"
377,P32P2,"In a retrospective study, ten patients with primary PCa underwent MP-MRI and PSMA-PET/CT for initial staging. All tumors were proven histopathologically by biopsy. Image analysis was done in a quantitative (SUVmax) and qualitative (blinded read) fashion based on PI-RADS. The PI-RADS schema was then translated into a 3D-matrix and the Euclidian distance of this coordinate system was used to quantify the extent of agreement.","[{'e1': 'ten patients with primary PCa ', 'e2': 'MP-MRI and PSMA-PET/CT ', 'relation': 'underwent ', 'condition': 'for initial staging'}]"
378,P32P4,PSMA-PET/CT and MP-MRI correlated well with regard to tumor allocation in patients with a high pre-test probability for large tumors. Further research will be needed to evaluate its value in challenging situations such as prostatitis or after repeated negative biopsies.,"[{'e1': 'PSMA-PET/CT ', 'e2': 'tumor allocation ', 'relation': 'correlated well with regard to ', 'condition': 'in patients with a high pre-test probability for large tumors'}, {'e1': 'MP-MRI ', 'e2': 'tumor allocation ', 'relation': 'correlated well with regard to ', 'condition': 'in patients with a high pre-test probability for large tumors'}]"
379,P32P5,"Initial prostate cancer staging is an important diagnostic procedure for patient stratification. During the last years, non-invasive multi-parametric magnetic resonance imaging has been introduced and clinically well established for T-staging in prostate cancer patients. Multi-parametric magnetic resonance imaging (MP-MRI) includes several different MR sequences, i.e., T2w, DW, DCE-MRI and MRS. Due to a very high imaging data volume, reporting standards such as PI-RADS were introduced to harmonize image analysis and improve patient staging outcome.","[{'e1': ' non-invasive multi-parametric magnetic resonance imaging ', 'e2': 'T-staging ', 'relation': 'has been introduced and clinically well established for ', 'condition': 'in prostate cancer patients'}]"
380,P32P6,"Recently, prostate-specific membrane antigen (PSMA)-positron emission tomography-computed tomography (PET/CT) based on the ligand 68Ga-PSMA11 has shown the potential to improve the detection of metastatic spread of prostate cancer in patients with biochemical recurrence. In this setting, PSMA-PET/CT was found superior in comparison to contrast-enhanced CT and Choline-PET/CT with regard to lymph node involvement and detection of distant metastases. Phase-I/II data found PSMA-SPECT/CT with 99mTc-trofolastat (MIP-1404) is also promising for diagnostics of primary PCa. In contrast, data for T-staging with PSMA-PET/CT had not been reported yet. Thus, MRI is still considered as the gold standard for T-staging of PCa, due to the fact of detailed depiction of size, infiltration and adjacent organ involvement.","[{'e1': ' prostate-specific membrane antigen (PSMA)', 'e2': ' detection of metastatic spread of prostate cancer', 'relation': ' has shown the potential to improve the', 'condition': ' in patients with biochemical recurrence'}]"
381,P32P7,This retrospective study aimed to quantify the agreement of multi-parametric MRI and PSMA-PET/CT in T-staging.,"[{'e1': 'This retrospective study ', 'e2': 'the agreement of multi-parametric MRI and PSMA-PET/CT ', 'relation': 'aimed to quantify ', 'condition': 'in T-staging.'}]"
382,P32P8,"In conclusion, PSMA-PET/CT and MP-MRI correlated well in tumor allocation in patients with a high pre-test probability for large tumors. Further research will be needed to evaluate the advantages of PSMA-PET/CT in challenging situations (e.g., prostatitis, benign prostate hyperplasia or after repeated negative biopsies) or if patients truly benefit from the handling of PSMA-positive findings as dominant intraprostatic lesions during radiation therapy.","[{'e1': 'PSMA-PET/CT ', 'e2': 'in tumor allocation', 'relation': 'correlated well ', 'condition': ' in patients with a high pre-test probability for large tumors'}, {'e1': 'MP-MRI ', 'e2': 'in tumor allocation', 'relation': 'correlated well ', 'condition': ' in patients with a high pre-test probability for large tumors'}]"
383,P33P1,"In the postscreening era, physicians are in need of methods to discriminate aggressive from nonaggressive prostate cancer (PCa) to reduce overdiagnosis and overtreatment. However, studies have shown that prognoses (e.g., progression and mortality) differ even among individuals with similar clinical and pathological characteristics. Existing risk classifiers (TMN grading system, Gleason score, etc.) are not accurately enough to represent the biological features of PCa. Using new genomic technologies, novel biomarkers and classifiers have been developed and shown to add value to clinical or pathological risk factors for predicting aggressive disease. Among them, RNA testing (gene expression analysis) is useful because it can not only reflect genetic variations but also reflect epigenetic regulations. Commercially available RNA profiling tests (Oncotype Dx, Prolaris, and Decipher) have demonstrated strong abilities to discriminate PCa with poor prognosis from less aggressive diseases. For instance, these RNA profiling tests can predict disease progression in active surveillance patients or early recurrence after radical treatments. These tests may offer more dependable methods for PCa prognosis prediction to make more accurate and personal medical decisions.","[{'e1': 'novel biomarkers ', 'e2': ' clinical or pathological risk factors ', 'relation': ' have been developed and shown to add value to', 'condition': 'for predicting aggressive disease'}, {'e1': 'classifiers', 'e2': ' clinical or pathological risk factors ', 'relation': ' have been developed and shown to add value to', 'condition': 'for predicting aggressive disease'}, {'e1': 'RNA profiling tests', 'e2': 'disease progression ', 'relation': ' can predict ', 'condition': 'in active surveillance patients'}, {'e1': 'RNA profiling tests', 'e2': 'early recurrence ', 'relation': ' can predict ', 'condition': 'after radical treatments'}]"
384,P33P2,"Prostate cancer (PCa) has become the second leading cause of cancer-related death among men, with an estimated 914,000 new cases and 258,000 deaths worldwide every year. This makes PCa a major public health problem worldwide.","[{'e1': 'Prostate cancer (PCa) ', 'e2': 'cancer-related death', 'relation': 'has become the second leading cause of ', 'condition': ' among men'}]"
385,P33P4,"To address the issue of being unable to accurately predict PCa prognosis, novel biomarkers have been shown to determine whether PCa is aggressive and to predict poor prognosis. In addition, new approaches that utilize new genomic technologies can assess genetic alterations and epigenetic events. Among them, RNA testing (gene expression analysis) is considered highly useful, for reflecting not only genetic variations but also epigenetic regulations. Several RNA tests have been approved for clinical use in prostate cancer and have been found to add value to clinical and pathological risks for prostate cancer progression. In this review, we focus on the value of commercially available RNA profiling tests in precision medicine practice for PCa.","[{'e1': 'Several RNA tests ', 'e2': 'clinical use ', 'relation': 'have been approved for ', 'condition': 'in prostate cancer '}, {'e1': 'Several RNA tests ', 'e2': 'clinical and pathological risks', 'relation': 'have been found to add value to ', 'condition': ' for prostate cancer progression'}]"
386,P34P2,"Globally, PCa is the most common cancer among men, with an estimated 1 442 000 new cases in 2013. While most PCa patients have an indolent form of the disease that may not require treatment, about 10%–20% of men affected with PCa have an aggressive form of the disease that may progress to metastases and death, thus requiring more intensive therapies. The inability to reliably distinguish between these two forms of PCa early in the course of the disease has resulted in overtreatment of many and undertreatment of some cases. This is because all patients with PCa are treated similarly in most cases even though the underlying genetic causes of their PCa tumors are likely different.","[{'e1': ' PCa ', 'e2': ' 1 442 000 new cases ', 'relation': 'is the most common cancer among men, with an estimated', 'condition': 'in 2013'}]"
387,P34P4,"Delineating the genomic and molecular characteristics of various types of PCa at different stages can improve our ability to understand the mechanisms that drive reemergence as aggressive PCa from indolent tumors and progression of malignant tumors to advanced stages. Analyzing the relationships between genomic alterations and clinical parameters may lead to better molecular markers for more accurate patient stratification and personalized cancer care. Due to a broad coverage of topics by other articles in this special issue, this review primarily focuses on somatically acquired aberrations of genomic DNA in the tumor genome and highlights their potentials for use as molecular biomarkers for prognosis and prediction of clinical outcome.","[{'e1': 'Delineating the genomic and molecular characteristics of various types of PCa at different stages ', 'e2': 'mechanisms that drive reemergence as aggressive PCa ', 'relation': 'can improve our ability to understand the ', 'condition': 'from indolent tumors and progression of malignant tumors to advanced stages'}, {'e1': 'this review ', 'e2': 'genomic DNA ', 'relation': 'primarily focuses on somatically acquired aberrations of ', 'condition': 'in the tumor genome'}]"
388,P35P1,"We conducted multiple microarray datasets analyses from clinical and xenograft tumor tissues to search for disease progression-driving oncogenes in prostate cancer (PCa). Sperm-associated antigen 5 (SPAG5) attracted our attention. SPAG5 was recently identified as an oncogene participating in lung cancer and cervical cancer progression. However, the roles of SPAG5 in PCa progression remain unknown.","[{'e1': 'SPAG5 ', 'e2': 'an oncogene participating ', 'relation': 'was recently identified as ', 'condition': 'in lung cancer and cervical cancer progression'}]"
389,P35P3,"We identified that SPAG5 expression was gradually increased in PCa progression and its level was significantly associated with lymph node metastasis, clinical stage, Gleason score, and biochemical recurrence. Our results indicated that SPAG5 knockdown can drastically inhibit PCa cell proliferation, migration, and invasion in vitro and suppress tumor growth and metastasis in vivo. We identified that miR-539 can directly target SPAG5. Ectopic overexpression of miR-539 can drastically inhibit SPAG5 expression and the restoration of SPAG5 expression can reverse the inhibitory effects of miR-539 on PCa cell proliferation and metastasis.","[{'e1': 'SPAG5 expression ', 'e2': 'lymph node metastasis', 'relation': 'was significantly associated with ', 'condition': ' in PCa progression'}, {'e1': 'SPAG5 expression ', 'e2': 'clinical stage', 'relation': 'was significantly associated with ', 'condition': ' in PCa progression'}, {'e1': 'SPAG5 expression ', 'e2': 'Gleason score', 'relation': 'was significantly associated with ', 'condition': ' in PCa progression'}, {'e1': 'SPAG5 expression ', 'e2': ' biochemical recurrence', 'relation': 'was significantly associated with ', 'condition': ' in PCa progression'}, {'e1': 'restoration of SPAG5 expression ', 'e2': ' miR-539 ', 'relation': 'can reverse the inhibitory effects of', 'condition': 'on PCa cell proliferation and metastasis.'}]"
390,P35P4,"Our results collectively showed a progression-driving role of SPAG5 in PCa which can be regulated by miR-539, suggesting that miR-539/SPAG5 can serve as a potential therapeutic target for PCa.","[{'e1': ' miR-539/SPAG5 ', 'e2': 'potential therapeutic target', 'relation': 'can serve as a ', 'condition': ' for PCa.'}]"
391,P35P5,"Prostate cancer (PCa) is one of the most common and aggressive human malignancies with poor prognosis worldwide. Although considerable advances in therapy and diagnosis of PCa have been made, many PCa patients will progress to castration-resistant PCa (CRPC) that is metastatic and shows resistance to hormonal therapy. Neuroendocrine PCa (NEPC) is another lethal form of PCa with most patients dying within 1 year of diagnosis despite very aggressive chemotherapeutic regimens. Increasing evidence indicates that prostatic adenocarcinoma can undergo a neuroendocrine transdifferentiation following long-term androgen deprivation therapy, and eventually progress to NEPC. However, NEPC studies have been hampered by a lack of clinically relevant in vivo models of the disease. Recently, our lab successfully generated a patient-derived xenograft model of complete neuroendocrine transdifferentiation (LTL331R) of a prostate adenocarcinoma (LTL331) at the Living Tumor Laboratory. Therefore, the NEPC xenograft model provides a valuable method for investigating the molecular mechanisms of NEPC progression. So discovery of new optimized therapeutic targets for more effective treatment of metastatic PCa, CRPC, and NEPC is urgently needed for improved disease management and patient survival.","[{'e1': 'prostatic adenocarcinoma ', 'e2': 'neuroendocrine transdifferentiation ', 'relation': 'can undergo a ', 'condition': 'following long-term androgen deprivation therapy'}]"
392,P35P6,"It is well known that sperm-associated antigen 5 (SPAG5) can bind to microtubules as a regulator of the timing of spindle organization and separation of sister chromatids. Previous studies indicated that SPAG5 was an important variable in mitosis and cell cycle checkpoint regulation. A previous study indicated that SPAG5 may act as a promoter in tumorigenesis and progression. Previous studies showed that SPAG5 overexpression can predict poor prognosis in lung cancer and cervical cancer and alter sensitivity to taxol treatment via the mTOR signaling pathway in cervical cancer. These results indicated that SPAG5 may act as an important oncogene that is involved in the formation and progression of malignancies and might influence the biological behaviors of malignancies. However, the molecular mechanism and role of SPAG5 in PCa development and progression have not yet been investigated.","[{'e1': 'SPAG5 overexpression ', 'e2': 'poor prognosis ', 'relation': 'can predict ', 'condition': 'in lung cancer '}, {'e1': 'SPAG5 overexpression ', 'e2': 'poor prognosis ', 'relation': 'can predict ', 'condition': 'in cervical cance'}, {'e1': 'SPAG5 overexpression ', 'e2': 'taxol treatment via the mTOR signaling pathway ', 'relation': ' alters sensitivity to ', 'condition': 'in cervical cancer'}, {'e1': 'SPAG5 ', 'e2': 'important oncogene that is involved ', 'relation': 'may act as an ', 'condition': 'in the formation and progression of malignancies'}]"
393,P35P9,"To our best knowledge, this is the first study to report the potential progression-driving function of SPAG5 in PCa. Our study also provides first experimental evidence that miR-539 can inhibit PCa cell growth and metastasis in PCa by directly repressing SPAG5. The newly identified miR-539/SPAG5 signal pathway may provide new insights into the progression of PCa and a potential therapeutic target for PCa treatment. Overall, the above results indicated that SPAG5 may play a progression-driving role in PCa and could serve as a viable therapeutic target.","[{'e1': ' miR-539 ', 'e2': 'PCa cell growth and metastasis ', 'relation': 'can inhibit ', 'condition': 'in PCa by directly repressing SPAG5'}]"
394,P36P3,Publicly accessible human prostate cancer expression arrays as well as RNA sequencing data from the prostate TCGA. Tumour-associated PSA and PSAD were calculated for a large cohort of men (n = 1108) undergoing prostatectomy.,"[{'e1': ' Tumour-associated PSA ', 'e2': ' a large cohort of men', 'relation': ' were calculated for', 'condition': 'undergoing prostatectomy.'}, {'e1': 'PSAD', 'e2': ' a large cohort of men', 'relation': ' were calculated for', 'condition': 'undergoing prostatectomy.'}]"
395,P36P4,"We performed a meta-analysis of the expression of an androgen-regulated gene set across datasets using Oncomine. Differential expression of selected genes in the prostate TCGA database was probed using the edgeR Bioconductor package. Changes in tumour PSA density with stage and grade were assessed by Student’s t-test, and its association with biochemical recurrence explored by Kaplan-Meier curves and Cox regression.","[{'e1': ' Differential expression of selected genes', 'e2': 'the edgeR Bioconductor package', 'relation': ' was probed using ', 'condition': ' in the prostate TCGA database'}]"
396,P36P7,"The androgen receptor (AR) is a ligand-activated transcription factor that is central to the initiation and progression of prostate cancer. The importance of AR signalling is underscored by the clinical utility of castration in producing symptomatic relief and objective responses in men with advanced prostate cancer. During prostate development, AR activation is known to increase the expression of growth factors, transcription factors and signalling peptides that are involved in cell proliferation, resistance to apoptosis, invasion and migration, processes which are necessary for successful organogenesis and are subsequently exploited by cancer. The expression of AR has been demonstrated to increase with increasing tumour grade and stage, as do serum levels of prostate specific antigen (PSA), the product of the prototypical androgen responsive gene KLK3. In fact, the positive relationship between increasing serum PSA and increasing tumour stage and grade informs all aspects of its usage in the clinical management of prostate cancer patients. However, it has been recognised for some time that there exists a small cohort of patients with primary prostate cancer that remains localised to the prostate, in whom serum PSA does not accurately reflect the extent of their disease burden. These ‘low-secreting’ tumours are reported to have a worse prognosis compared to grade- and stage-matched controls. This is supported by a number of studies indicating that the incidence of prostate cancer, including high-grade tumours, is significant in patients with serum PSA levels within the quoted normal range.","[{'e1': ' AR activation ', 'e2': 'expression of growth factors', 'relation': 'is known to increase the ', 'condition': 'During prostate development,'}, {'e1': ' AR activation ', 'e2': 'expression of transcription factors ', 'relation': 'is known to increase the ', 'condition': 'During prostate development,'}, {'e1': ' AR activation ', 'e2': 'expression of signalling peptides', 'relation': 'is known to increase the ', 'condition': 'During prostate development,'}, {'e1': 'clinical utility of castration', 'e2': 'symptomatic relief and objective responses ', 'relation': ' in producing ', 'condition': 'in men with advanced prostate cancer'}]"
397,P37P5,"Prostate cancer (PC) is the most commonly diagnosed malignancy and the fifth leading cause of cancer-related death among males in western countries. PC is diagnosed by histological inspection of prostate needle biopsies, generally indicated by an elevated serum prostate specific antigen (PSA) test and/or a suspect digital rectal examination (DRE). However, PSA has low specificity for PC while biopsies have high false negative rates and often must be repeated. Moreover, currently available prognostic indicators (mainly PSA, Gleason score and tumor stage) cannot accurately predict PC aggressiveness at the time of diagnosis, which has led to overtreatment of many indolent PCs partly as a result of increased PSA testing. There is an urgent need for new molecular biomarkers that can improve the accuracy of PC detection and better distinguish aggressive PCs that need immediate treatment, e.g. by radical prostatectomy (RP), from non-aggressive PCs that can be safely managed by active surveillance.","[{'e1': 'Prostate cancer (PC) ', 'e2': 'cancer-related death ', 'relation': ' is the fifth leading cause of ', 'condition': 'among males in western countries'}, {'e1': ' prognostic indicators ', 'e2': ' PC aggressiveness ', 'relation': 'cannot accurately predict', 'condition': 'at the time of diagnosis'}]"
398,P37P6,"In this study, we investigate the diagnostic and prognostic biomarker potential of microRNAs (miRNAs) for PC. MicroRNAs comprise an abundant class of endogenous small non-coding RNAs (~22-nt) that control gene expression at the posttranscriptional level. MicroRNAs are transcribed by RNA polymerase II into long, imperfectly paired stem-loop primary miRNAs, which are further processed into hairpin-containing precursor miRNAs, exported to the cytoplasm, and cleaved into a mature ~22-nt miRNA duplex. Mature miRNAs guide the miRNA-induced silencing complex (miRISC) to perfect or near-perfect complementary target mRNAs, resulting in translational inhibition or mRNA degradation. It has been estimated that up to 60% of human mRNAs are regulated by miRNAs, often in a highly cell type-specific manner, and miRNAs are known to influence key cellular processes, e.g. differentiation, cell cycle progression, and apoptosis.","[{'e1': 'MicroRNAs comprise an abundant class of endogenous small non-coding RNAs (~22-nt) ', 'e2': 'gene expression', 'relation': 'that control ', 'condition': ' at the posttranscriptional level'}]"
399,P37P7,"Deregulated miRNA expression has been associated with malignant transformation and tumor progression in several cancer types. Thus, previous profiling studies have identified deregulated miRNAs associated with PC development and/or progression, but with little overlap in identified miRNAs. Still, downregulation in PC tissue of miR-125b, miR-205, and the miR-221/222 cluster as well as upregulation of miR-21, miR-375, and the miR-200 family have been consistently reported. However, most earlier studies, and especially those focusing on prognostic markers, have generally used relatively small patient sample sets and/or lack sufficient independent clinical validation.","[{'e1': 'Deregulated miRNA expression ', 'e2': 'malignant transformation ', 'relation': 'has been associated with ', 'condition': ' in several cancer types'}, {'e1': 'Deregulated miRNA expression ', 'e2': 'tumor progression', 'relation': 'has been associated with ', 'condition': ' in several cancer types'}]"
400,P37P8,"In the present study, we used three independent PC patient cohorts to identify and validate novel diagnostic and prognostic miRNA candidate markers for PC. Initially, using a training cohort, we employed global miRNA analysis to identify differentially expressed miRNAs between non-malignant and PC tissue samples and between clinically relevant subgroups of PC. Moreover, we trained and validated two new miRNA signatures with improved diagnostic and prognostic performance as compared to single miRNAs. Thus, a novel 13-miRNA diagnostic classifier distinguished non-malignant and PC samples with very high accuracy in a training set (n = 147) and was successfully validated in a large independent patient sample set (n = 157). Furthermore, a novel 3-miRNA prognostic classifier predicted biochemical recurrence (BCR) risk after RP independently of routine clinicopathological parameters in a training cohort (n = 126) as well as in two independent validation cohorts (n = 110/n = 99).","[{'e1': 'a novel 3-miRNA prognostic classifier ', 'e2': 'biochemical recurrence (BCR) risk ', 'relation': 'predicted ', 'condition': 'after RP'}]"
401,P37P9,"In conclusion, we have shown that the combination of multiple miRNAs into molecular classifiers may improve the diagnostic and prognostic biomarker potential of miRNAs for PC. In order to translate our new diagnostic and prognostic miRNA classifiers into potential future clinical use, they must be further validated in multi-center studies using large, well-characterized patient cohorts and clearly defined clinical endpoints. Future studies should also assess their potential for non- or minimally invasive testing in urine and blood samples.","[{'e1': 'combination of multiple miRNAs into molecular classifiers ', 'e2': 'diagnostic and prognostic biomarker potential ', 'relation': 'may improve the ', 'condition': 'of miRNAs for PC'}]"
402,P38P1,"We evaluated gene expression in histologically normal-appearing tissue adjacent to prostate tumor in radical prostatectomy specimens, assessing for biological significance based on prediction of clinical recurrence (cR - metastatic disease or local recurrence).","[{'e1': 'expression in histologically normal-appearing tissue ', 'e2': 'prostate tumor ', 'relation': 'adjacent to ', 'condition': 'in radical prostatectomy specimens'}]"
403,P38P2,"A total of 410 evaluable patients had paired tumor and NT. Forty-six genes, representing diverse biological pathways (androgen signaling, stromal response, stress response, cellular organization, proliferation, cell adhesion, and chromatin remodeling) were associated with cR in NT (FDR < 20%), of which 39 concordantly predicted cR in tumor (FDR < 20%). Overall GPS and its stromal response and androgen-signaling gene group components also significantly predicted time to cR in NT (RM-corrected HR/20 units = 1.25; 95% CI: 1.01‚àí1.56; P = 0.024).","[{'e1': 'Forty-six genes, representing diverse biological pathways ', 'e2': ' cR', 'relation': 'were associated with', 'condition': ' in NT'}, {'e1': '39 genes', 'e2': 'cR ', 'relation': ' concordantly predicted ', 'condition': 'in tumor'}, {'e1': ' Overall GPS and its stromal response and androgen-signaling gene group components ', 'e2': 'time to cR ', 'relation': 'also significantly predicted ', 'condition': 'in NT'}]"
404,P38P3,"Expression of 732 genes was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) separately in tumor and adjacent NT specimens from 127 patients with and 374 without cR following radical prostatectomy for T1/T2 prostate cancer. A 17-gene expression signature (Genomic Prostate Score [GPS]), previously validated to predict aggressive prostate cancer when measured in tumor tissue, was also assessed using pre-specified genes and algorithms. Analysis used Cox proportional hazards models, Storey’s false discovery rate (FDR) control, and regression to the mean (RM) correction.","[{'e1': 'Expression of 732 genes ', 'e2': 'separately in tumor and adjacent NT specimens ', 'relation': 'was measured', 'condition': 'following radical prostatectomy for T1/T2 prostate cancer'}]"
405,P38P5,"There is a clear medical need for prostate cancer (PCa) biomarkers that provide accurate risk stratification to inform clinical decision making for men with newly diagnosed disease. The intrinsic heterogeneity and multifocal nature of PCa have challenged the development of robust molecular markers. One approach to addressing these challenges is to incorporate a deeper understanding of the biology of the non-malignant cells present within and adjacent to the tumor, which may represent a generalized field effect related to tumor aggressiveness. The concept of field cancerization has evolved from a histological definition first credited to Slaughter et al. in 1953 to a molecular definition exemplified by a range of genetic and epigenetic abnormalities that can be detected in normal-appearing tissues (NT) adjacent to cancers, including gene silencing by methylation, deletions in mitochondrial DNA, mutations in cancer-related genes, and aberrant gene expression. Evidence for a field effect has been reported in a variety of cancer types, including head and neck, lung, colon, breast, stomach, bladder and PCa.","[{'e1': ' prostate cancer (PCa) biomarkers ', 'e2': ' accurate risk stratification to inform clinical decision making ', 'relation': 'that provide', 'condition': 'for men with newly diagnosed disease'}]"
406,P38P6,"We undertook a series of studies to develop a tumor-based gene expression signature that would provide a biologic measure of tumor aggressiveness and improve risk assessment for men with newly diagnosed, clinically low-risk PCa. As previously described, we screened the expression of 732 cancer-related genes in radical prostatectomy (RP) tumor specimens from 441 patients with clinically localized disease, and identified genes whose expression was predictive of clinical outcome. To create an assay that was a robust predictor of outcome in the face of heterogeneity in grade and multifocality, we selected genes that were predictive of clinical recurrence (metastases or locoregional recurrence) in two separate regions of each tumor. From those studies, we identified a final set of 12 cancer-related genes, representing several biological pathways, and 5 reference genes which were combined in an algorithm to generate a 100-point Genomic Prostate Score (GPS). The clinical-grade assay has been analytically and clinically validated to predict the likelihood of adverse pathology at radical prostatectomy and risk of biochemical recurrence when performed on RNA from fixed paraffin-embedded prostate needle biopsy specimens. The assay has been shown to influence clinical decision making by distinguishing men with biologically non-aggressive tumors who are appropriate candidates for active surveillance from men with clinically low risk disease who have biologically aggressive tumors and should be considered for immediate therapy.","[{'e1': ' a series of studies to develop a tumor-based gene expression signature', 'e2': 'a biologic measure of tumor aggressiveness ', 'relation': ' that would provide ', 'condition': 'for men with newly diagnosed, clinically low-risk PCa'}, {'e1': ' a series of studies to develop a tumor-based gene expression signature', 'e2': 'risk assessment ', 'relation': 'that would improve ', 'condition': 'for men with newly diagnosed, clinically low-risk PCa'}, {'e1': 'genes ', 'e2': 'clinical recurrence ', 'relation': 'that were predictive of ', 'condition': 'in two separate regions of each tumor'}]"
407,P38P7,"A pre-specified aim of the original gene identification study conducted on RP specimens was to assess gene expression in NT adjacent to prostate tumor, where “adjacent” was defined as ≥3-mm distant from tumor. The goal of this analysis was to identify gene expression changes in NT that could predict clinical outcome and to compare the gene expression patterns from NT to tumor tissue. Additionally, post-hoc analyses were conducted to evaluate if GPS, developed using the tumor-containing tissue, was predictive of outcome when applied to gene expression derived from NT specimens. In this study we asked whether identification of genes in NT would provide evidence for a biologically meaningful field effect in the tumor-containing prostate and identify early markers of aggressive PCa assayable in non-tumor tissue.","[{'e1': 'the original gene identification study conducted on RP specimens ', 'e2': 'gene expression ', 'relation': 'was to assess ', 'condition': 'in NT adjacent to prostate tumor'}, {'e1': 'identification of genes in NT', 'e2': 'biologically meaningful field effect ', 'relation': ' would provide evidence for a ', 'condition': 'in the tumor-containing prostate '}, {'e1': 'identification of genes in NT', 'e2': 'aggressive PCa assayable', 'relation': 'would identify early markers of ', 'condition': ' in non-tumor tissue.'}]"
408,P39P3,"In 1004 PCs (~4,000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage, seminal vesicle invasion (SVI), extracapsular extension (ECE) and Gleason Score (GS). Ki67 PI as a continuous variable significantly correlated with recurrence free, overall and disease-specific survival by multivariable Cox proportional hazard model (HR=1.04–1.1, p=0.02–0.0008). High Ki67 score (defined as ≥5%) was significantly associated with worse recurrence free survival (HR=1.47, p=0.0007) and worse overall survival (HR=2.03, p=0.03).","[{'e1': 'Ki67 PI ', 'e2': ' recurrence free, overall and disease-specific survival ', 'relation': 'correlated with', 'condition': 'by multivariable Cox proportional hazard model'}]"
409,P39P4,"In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE, and greater probability of recurrence.","[{'e1': ' higher Ki67 PI assessed using a clinical grade automated algorithm ', 'e2': ' a higher GS', 'relation': 'is strongly associated with', 'condition': 'In localized PC treated by radical prostatectomy'}, {'e1': ' higher Ki67 PI assessed using a clinical grade automated algorithm ', 'e2': 'stage', 'relation': 'is strongly associated with', 'condition': 'In localized PC treated by radical prostatectomy'}, {'e1': ' higher Ki67 PI assessed using a clinical grade automated algorithm ', 'e2': 'SVI and ECE', 'relation': 'is strongly associated with', 'condition': 'In localized PC treated by radical prostatectomy'}, {'e1': ' higher Ki67 PI assessed using a clinical grade automated algorithm ', 'e2': ' greater probability of recurrence.', 'relation': 'is strongly associated with', 'condition': 'In localized PC treated by radical prostatectomy'}]"
410,P39P6,"The Canary Tissue Microarray of Prostate cancer outcomes (CTMAP) was designed with the primary objective of validating promising candidate biomarkers reported to predict PC recurrence at the time of radical prostatectomy (RP). The CTMAP model of a case-cohort study was designed to allow validation of a biomarker with approximately two-fold sensitivity greater than Gleason score (GS) in predicting PC recurrence. Such a marker would likely benefit clinical practice. Oversampling of recurrent low-grade tumors and non-recurrent high-grade tumors in CTMAP decreases the influence of GS, allowing unbiased validation of independent prognostic biomarkers. This large and well-annotated tissue resource of more than 1,300 randomly selected RP specimens with prolonged follow-up from six academic institutions also reflects the heterogeneity of PC and spectrum of patient management in North America.","[{'e1': 'The Canary Tissue Microarray of Prostate cancer outcomes (CTMAP) ', 'e2': 'validating promising candidate biomarkers reported to predict PC recurrence ', 'relation': 'was designed with the primary objective of ', 'condition': 'at the time of radical prostatectomy (RP)'}, {'e1': ' The CTMAP model of a case-cohort study', 'e2': 'validation of a biomarker with approximately two-fold sensitivity greater than Gleason score (GS)', 'relation': ' was designed to allow ', 'condition': ' in predicting PC recurrence'}, {'e1': 'This large and well-annotated tissue resource of more than 1,300 randomly selected RP specimens ', 'e2': ' PC ', 'relation': 'also reflects the heterogeneity of', 'condition': ' in North America.'}, {'e1': 'This large and well-annotated tissue resource of more than 1,300 randomly selected RP specimens ', 'e2': 'patient management', 'relation': 'also reflects the spectrum of ', 'condition': ' in North America.'}]"
411,P39P9,"In localized PC treated by radical prostatectomy, Ki67 PI provides independent prognostic value for RFS, DSS and OS beyond Gleason score, pathological stage and PSA levels. In our large, multi-institutional cohort, Ki67 PI performed best as a continuous variable and could be incorporated into existing or new predictive nomograms. Additionally, our study suggests that risk stratification for localized PC could be achieved with Ki67 as a dichotomous variable at 5% cutoff. These findings strongly suggest that Ki67 PI should be further tested as a prognostic biomarker in other clinically relevant cohorts such as patients on active surveillance, and possibly in patients undergoing image guided biopsies.","[{'e1': 'Ki67 PI ', 'e2': ' RFS', 'relation': 'provides independent prognostic value for', 'condition': 'In localized PC treated by radical prostatectomy,'}, {'e1': 'Ki67 PI ', 'e2': 'DSS and OS beyond Gleason score', 'relation': 'provides independent prognostic value for', 'condition': 'In localized PC treated by radical prostatectomy,'}, {'e1': 'Ki67 PI ', 'e2': 'pathological stage ', 'relation': 'provides independent prognostic value for', 'condition': 'In localized PC treated by radical prostatectomy,'}, {'e1': 'Ki67 PI ', 'e2': 'PSA levels', 'relation': 'provides independent prognostic value for', 'condition': 'In localized PC treated by radical prostatectomy,'}, {'e1': ' Ki67 PI', 'e2': ' a prognostic biomarker ', 'relation': ' should be further tested as', 'condition': 'in other clinically relevant cohorts such as patients on active surveillance'}, {'e1': ' Ki67 PI', 'e2': ' a prognostic biomarker ', 'relation': ' should be further tested as', 'condition': ' in patients undergoing image guided biopsies.'}]"
412,P40P2,"A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for prostate cancer outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions by smoking status. To select potential functionally relevant differentially methylated regions, their correlation with the messenger RNA expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked differentially methylated regions was created to assess its association with prostate cancer outcomes.","[{'e1': ' A methylome-wide analysis', 'e2': 'differentially methylated regions', 'relation': ' was conducted to identify ', 'condition': ' by smoking status'}]"
413,P40P5,"More than 200,000 men are diagnosed with prostate cancer each year in the United States, and there are approximately 3 million US men living with the disease. Increasing evidence links smoking with more aggressive prostate cancer and disease mortality; however, the specific biological processes driving this association are unclear.","[{'e1': 'More than 200,000 men ', 'e2': 'prostate cancer each year ', 'relation': 'are diagnosed with ', 'condition': 'in the United States'}]"
414,P40P7,"Although these results are intriguing, most studies to date have assessed methylation profiles with DNA isolated from blood. We are not aware of any studies that have quantified the relation between smoking and methylome-wide DNA alterations in primary prostate tumor tissue. In addition, although a role for methylation in mediating the relation between smoking and cancer progression has been hypothesized, only a few studies of DNA methylation, interrogating a limited number of candidate genes, have been reported. Our group and others have previously shown that smoking is associated with a significant increase in prostate cancer progression and mortality. In this study, we build on those findings and aim to comprehensively assess differences in tumor methylation profiles by smoking status, determine whether the smoking-associated methylation alterations are related to changes in messenger RNA expression, and test whether these smoking-associated alterations in DNA methylation are related to prostate cancer prognosis.","[{'e1': ' smoking ', 'e2': 'a significant increase ', 'relation': 'is associated with ', 'condition': 'in prostate cancer progression and mortality'}]"
415,P40P8,"In summary, our results provide support for the hypothesis that smoking-induced changes in DNA methylation may underlie the association of smoking with prostate cancer recurrence and mortality. We found that smoking was associated with differential methylation profiles in prostate tumor tissue and that several of the differentially methylated regions encompassed genes with associated changes in messenger RNA expression and were associated with more aggressive tumor characteristics at diagnosis and adverse outcomes. Clearly, the prevention of smoking or smoking cessation is recommended for prostate health and overall health in general. However, knowledge of the molecular mechanisms underlying the association of smoking and prostate cancer outcomes may provide clues about prostate cancer aggressiveness and help in identifying strategies for aiding the many prostate cancer survivors who are unable to quit. There are currently several promising therapies that can alter methylation profiles, and this highlights the translational potential for better understanding the role of DNA methylation in prostate cancer progression. Thus, future studies are warranted to confirm these findings and to assess their implications for clinical translation. In the meantime, these results highlight the adverse effects of smoking on prostate cancer prognosis and the need for effective smoking cessation strategies.","[{'e1': 'smoking ', 'e2': 'differential methylation profiles ', 'relation': 'was associated with ', 'condition': 'in prostate tumor tissue'}, {'e1': 'several of the differentially methylated regions ', 'e2': 'more aggressive tumor characteristics', 'relation': 'were associated with ', 'condition': ' at diagnosis and adverse outcomes'}, {'e1': 'the translational potential ', 'e2': 'DNA methylation', 'relation': 'for better understanding the role of ', 'condition': ' in prostate cancer progression'}]"
416,P41P2,"In the United States, approximately 220,800 men are diagnosed with prostate cancer (PCa) and more than 27,000 men die from the disease annually. The optimal management strategy for this tumor is a subject of continuous debate. Physicians face many challenges in treating PCa, primarily because of the apparent heterogeneity of the disease, which acts differently in each patient. Although there is a concern of overdiagnosis and overtreatment of many men with low-risk tumors, many others with high-risk tumors are likely undertreated. Moreover, in cases in which active treatment is indicated, the optimal initial treatment strategy and the most appropriate sequence of treatments are not always clear. Likewise, the most appropriate management strategy for patients with metastatic and castration-resistant disease is a subject of controversy and continuous research.","[{'e1': ' approximately 220,800 men ', 'e2': 'prostate cancer (PCa) ', 'relation': 'are diagnosed with ', 'condition': 'In the United States,'}]"
417,P41P3,"These uncertainties in treating PCa are mainly derived by our inability to accurately identify the natural history and aggressiveness of the tumor at an individualized level. To address this issue, many PCa classification systems have been proposed, such as TNM staging, Gleason score grading, D’Amico risk stratification, the University of California, San Francisco-Cancer of the Prostate Risk Assessment (CAPRA) score, and many others. Although these models have improved our ability to evaluate and predict the aggressiveness of PCa, their performance in many cases is still suboptimal. This may stem from the fact that these models rely heavily on the macro- and microscopic features of the tumor, which can be misleading. Further, current risk prediction methods are limited because they are unable to distinguish individual risk for patients who present with similar pathology. To overcome this limitation, genomic markers have been proposed as a complementary tool to these models. These markers offer the advantage of capturing information that is beyond the reach of the routinely available clinical and pathologic characteristics of the disease, such as tumor stage, grade, and prostate-specific antigen (PSA) value. This will likely revolutionize the way we approach PCa, and allow us to conquer new territories in our continuous fight against this disease. The objective of this review is to assess the role of one of the most promising genomic biomarkers, Decipher (GenomeDx Biosciences, San Diego, CA), in staging/grading and managing PCa.","[{'e1': ' uncertainties in treating PCa ', 'e2': 'natural history and aggressiveness of the tumor ', 'relation': 'are mainly derived by our inability to accurately identify the ', 'condition': 'at an individualized level.'}]"
418,P41P5,"Prostate cancer (PCa) is the second most prevalent oncologic disease among men worldwide. Expression of various transcripts, including miRNAs, is markedly deregulated in cancerous prostate tissue. This study aimed at identifying a PCa-specific expression profile of miRNAs for subsequent use in noninvasive diagnostics.","[{'e1': ' Expression of various transcripts', 'e2': ' deregulated ', 'relation': ' is markedly', 'condition': 'in cancerous prostate tissue. '}]"
419,P41P7,"Analysis of miRNA expression in prostate tissue linked miR-95 to aggressive form of PCa. This miRNA was up-regulated in high grade, the TMPRSS2-ERG fusion-positive tumors, and in patients with subsequently developed biochemical recurrence (BCR) after radical prostatectomy. MiRNAs highly expressed in PCa tissues were also detectable in urine from PCa patients. Moreover, the urinary levels of miR-21 had significant discriminatory power to separate PCa patients from BPH, while the combined analysis of urinary miR-19a and miR-19b was prognostic for BCR. In PCa, the diagnostic potential of urinary miRNA panel (miR-21, miR-19a, and miR-19b) was higher than that of the PSA test (AUC = 0.738 vs. AUC = 0.514).","[{'e1': 'Analysis of miRNA expression ', 'e2': 'aggressive form of PCa', 'relation': ' linked miR-95 to ', 'condition': 'in prostate tissue'}, {'e1': 'patients ', 'e2': ' biochemical recurrence (BCR)', 'relation': 'developed', 'condition': ' after radical prostatectomy'}, {'e1': ' MiRNAs ', 'e2': ' PCa tissues were also detectable ', 'relation': 'highly expressed in', 'condition': 'in urine from PCa patients'}]"
420,P44P4,"In conclusion, HELLS and ZIC5 might be promising candidate markers for selection of biopsy GS 6 prostate cancer being at risk for up-grading at prostatectomy.","[{'e1': 'HELLS and ZIC5', 'e2': 'selection of biopsy GS 6 prostate cancer being at risk for up-grading ', 'relation': ' might be promising candidate markers for ', 'condition': 'at prostatectomy.'}]"
421,P44P6,"While GS 6 prostate cancer demonstrates an indolent disease course in many patients, 55–90% of patients still undergo radical prostatectomy. A widely used alternative to surgery is active surveillance. Up to 33% of patients on active surveillance, however, will eventually undergo therapeutic intervention after a median follow-up of 1–4 years. Therefore, more accurate stratification of GS 6 prostate cancer patients is needed. A caveat of current Gleason grading on diagnostic biopsies is sampling artifact. Up to 38% of the patients with GS 6 prostate cancer on biopsy has GS ≥ 7 at subsequent radical prostatectomy. To optimize treatment decisions, it is essential to identify patients at risk for tumor under-grading at diagnosis.","[{'e1': ' GS 6 prostate cancer ', 'e2': 'an indolent disease course', 'relation': 'demonstrates ', 'condition': ' in many patients'}]"
422,P44P7,"GS 7 prostate cancer is composed of a mixture of regular tumor glands (Gleason grade 3) and aberrant glandular tumor structures (Gleason grade 4). Due to tumor heterogeneity, diagnostic biopsies might only sample Gleason grade 3 tumor areas leaving clinically relevant Gleason grade 4 patterns undiscovered. We hypothesize that Gleason grade 3 tumor glands embedded in GS 7 prostate cancer have different molecular expression profiles than Gleason grade 3 tumor glands embedded in GS 6 cancer.","[{'e1': 'Gleason grade 3 tumor glands embedded in GS 7 prostate cancer', 'e2': 'Gleason grade 3 tumor glands embedded', 'relation': ' have different molecular expression profiles than ', 'condition': ' in GS 6 cancer.'}]"
423,P45P10,"Of the different epigenetic marks, our understanding of the mechanisms by which DNA methylation alterations are heritably maintained, via the action of “preservers,” across DNA replication and cell division is most mature. As discussed above, DNMT1 can track with the replication fork and has strong catalytic activity for methylating the daughter strand when the parent strand is methylated at a CpG dinucleotide. In addition, the UHRF1 protein, which is expressed during S phase, can bind hemimethylated DNA at the replication fork and can recruit DNA methyltransferases to those sites to enforce maintenance of methylation during replication. With these mechanisms combined, there appears to be a robust potential for maintaining DNA methylation in human cells. Interestingly, for other epigenetic marks, such as histone modifications, the best-known mechanisms for maintenance across replication involve signaling and reinforcement by DNA methylation. For example, UHRF1 can also recruit the G9A histone methyltransferase to methylate H3K9 at sites of DNA methylation across replication. Such mechanisms closely link the various epigenetic marks to mediate a unified and cooperative epigenetic code.","[{'e1': ' the UHRF1 protein ', 'e2': 'hemimethylated DNA ', 'relation': 'can bind ', 'condition': 'at the replication fork '}]"
424,P45P2,"The field of epigenetics, once a very specialized area of study only undertaken by specialists, has now come to pervade nearly all fields of study in biomedical research. This is in large part because of the increasing recognition of the importance of epigenetics to health and disease. Along with this increased awareness, however, there is often some confusion as to what exactly epigenetics refers to. We will begin this chapter with a brief overview of the basic concepts and principles of epigenetics, and then delve into recent insights on prostate cancer epigenetics and their potential for translation to biomarkers and therapeutic strategies.","[{'e1': 'The field of epigenetics ', 'e2': 'nearly all fields of study ', 'relation': 'has now come to pervade ', 'condition': 'in biomedical research'}]"
425,P45P6,"Methylation of the 5-position of the cytosine base is an important epigenetic mark in human DNA, and highly conserved through vertebrates; plants and other eukaryotes also utilize such cytosine methylation-based epigenetic regulation. In normal adult cells, the majority of 5-methylcytosine marks occurs in the context of cytosine-phospho-guanine dinucleotides, with more than 80% of such CpGs typically being methylated. While cytosines in other sequence contexts can occur relatively frequently in embryonic stem cells, such non-CpG methylation usually accounts for less than 1% of overall cytosine methylation in the majority of adult cell types studied but may have some functional significance despite its low abundance. CpG methylation in normal cells is typically excluded from CpG dense regions in the genome called CpG islands that are often found around transcriptional start sites of genes and other regulatory regions. In cancer cells, these CpG islands, and regions with a lower CpG density around these CpG islands, called “CpG island shores,” can be abnormally hypermethylated in cancer cells compared to normal cell counterparts. This CpG island hypermethylation is often associated with repression of the nearby gene and has become recognized as a major mechanism of epigenetic gene repression that is particularly associated with silencing of cancer-protective genes as well as genes involved in development and differentiation in cancer cells. This DNA hypermethylation-mediated gene repression can be quite stable, inactivating genes in a manner analogous to genetic loss of function mutations and deletions. Paradoxically, in parallel with development of DNA hypermethylation-mediated epigenetic repression at CpG islands and shores around gene regulatory regions, cancer cells can also show progressive hypomethylation of many CpG dinucleotides. In large stretches of genomic DNA often spanning many hundreds of kilobases to megabases, where normal cells harbor a high degree of CpG methylation, cancer cells often exhibit diminished methylation. While this type of hypomethylation does not seem to lead to activation of genes nearby with any consistency, it is thought that such genomic blocks of hypomethylation can be associated with more open chromatin in cancer cells, leading to genomic instability. In addition, this hypomethylation has been associated with activation of endogenous retroviral elements, retrotransposons, and other repetitive sequences, further contributing to genomic instability.","[{'e1': ' majority of 5-methylcytosine marks ', 'e2': 'cytosine-phospho-guanine dinucleotides', 'relation': 'occurs in the context of ', 'condition': ' In normal adult cells'}, {'e1': ' non-CpG methylation ', 'e2': 'less than 1% of overall cytosine methylation', 'relation': 'usually accounts for ', 'condition': ' in the majority of adult cell types studied'}, {'e1': 'CpG islands, and regions with a lower CpG density around these CpG islands, called “CpG island shores,” ', 'e2': 'cancer cells compared to normal cell counterparts', 'relation': 'can be abnormally hypermethylated in ', 'condition': ' In cancer cells'}, {'e1': ' a major mechanism of epigenetic gene repression ', 'e2': 'silencing of cancer-protective genes as well as genes involved in development and differentiation', 'relation': 'that is particularly associated with ', 'condition': ' in cancer cells'}, {'e1': 'genomic blocks of hypomethylation ', 'e2': 'more open chromatin ', 'relation': 'can be associated with ', 'condition': 'in cancer cells'}]"
426,P45P8,"DNA methylation can also be actively “erased,” presumably independent of DNA replication. Such active reversal of DNA methylation has been suggested to play an important role in mediating plasticity and dynamic epigenetic regulation, particularly in certain cell types such as neurons and embryonic stem cells. Recent work has implicated oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine by ten-eleven translocation family proteins, encoded by three distinct genes such as TET1, TET2, and TET3. Although the precise mechanism of active demethylation by such oxidation has not been fully worked out, it appears that the oxidized forms are either directly excised by DNA glycosylases such as TDG and replaced with unmethylated cytosine by base excision repair machinery or are first deaminated prior to excision and base excision repair. Haffner and colleagues were the first to show robustly that when compared to normal differentiated or effector cells in many tissue types, the abundance of 5-hydroxymethylcytosine, which is the major oxidized form of 5-methylcytosine, is profoundly reduced in human cancers, including prostate cancer, and stem or progenitor cell compartments. This finding has now been reproduced by numerous labs for a multitude of cancer types. We speculate that this loss of 5-hydroxymethylcytosine in cancer cells might indicate a reduced plasticity of DNA methylation alterations in human cancer.","[{'e1': 'loss of 5-hydroxymethylcytosine in cancer cells ', 'e2': 'DNA methylation alterations', 'relation': 'might indicate a reduced plasticity of ', 'condition': ' in human cancer.'}]"
427,P45P9,"Among the “readers” of DNA methylation marks are specialized methyl-binding domain proteins capable of selectively binding methylated DNA and recruiting corepressor complexes such as Mi2-NURD to those sites to transduce the DNA methylation signal and produce repressive chromatin. In human cells, there are five well-characterized methyl-binding domain proteins, encoded by MBD1, MBD2, MBD3, MBD4, and MECP2. Of these, MBD1, MBD2, and MECP2 show high affinity for methylated CpG dinucleotides in double-stranded DNA. Although MBD3 is highly homologous to MBD2, it does not display affinity for methylated DNA but is thought to be an integral member of corepressor complexes involved in repressing chromatin. A recent study has suggested that MBD3 may bind hydroxymethylated DNA, but this has been controversial, and more recent work has implicated MECP2 as the major MBD protein capable of binding hydroxymethylcytosine marks, raising the possibility that hydroxymethylcytosine may not merely be an intermediate oxidized form leading to demethylation but may have its own signaling functions distinct from 5-methylcytosine. Finally, MBD4 has a glycosylase domain and is thought to be involved in base excision repair of T:G mismatches produced by deamination of 5-methylcytosine.","[{'e1': 'MBD1, MBD2, and MECP2 ', 'e2': 'methylated CpG dinucleotides', 'relation': 'show high affinity for ', 'condition': ' in double-stranded DNA'}]"
428,P46P2,"Prostate cancer (PC) remains one of the most common causes of male cancer deaths worldwide. Many patients with organ-confined tumors at initial diagnosis relapse following radical prostatectomy or local radiotherapy and develop recurrent disease. On a molecular level, the steroid hormone androgen activates the androgen receptor (AR), which in turn functions as a nuclear receptor transcription factor and executes specific tumorigenic gene-expression programs. Therefore, advanced cancer therapy includes androgen-deprivation approaches through inhibition of androgen synthesis and the administration of competitive AR antagonists. Unfortunately, most patients develop resistance to treatment and subsequently progress to castration-resistant disease (CRPC) that in most cases continues to rely on AR signaling. As CRPC is often fatal, there is a significant need for improved treatment options. How AR regulates CRPC growth is incompletely characterized, but has been reported to involve mechanisms that enable transactivation of AR under low androgen levels. Proposed processes include intratumoral production of androgens, genetic changes of the AR gene, the emergence of ligand-independent AR splice variants, crosstalk between AR and other signaling pathways, and the altered action of transcriptional co-regulators.","[{'e1': 'advanced cancer therapy ', 'e2': 'androgen-deprivation approaches ', 'relation': 'includes ', 'condition': 'through inhibition of androgen synthesis '}, {'e1': 'advanced cancer therapy ', 'e2': 'androgen-deprivation approaches ', 'relation': 'includes ', 'condition': 'through administration of competitive AR antagonists'}]"
429,P46P3,"Genome sequencing studies have revealed recurrent founder mutations in the substrate-binding cleft of the cullin-RING ubiquitin ligase adaptor speckle-type POZ protein (SPOP) in approximately 10% of primary PC. SPOP proteins harboring PC-specific mutations have been reported as being defective in mediating ubiquitylation and proteasomal degradation of AR and its co-activator NCOA3, and thus promote AR signaling. In agreement with this, enhanced AR signaling has been identified as a cardinal feature of SPOP mutant tumors. Using an unbiased proteomic approach in prostate epithelial cells, we identified TRIM24 (tripartite motif-containing protein 24, also known as TIF1a) as another potential effector protein downstream of SPOP mutations. Moreover, TRIM24 showed reduced ubiquitylation that was accompanied by increased protein levels in the presence of SPOP mutations.","[{'e1': 'Genome sequencing studies ', 'e2': 'recurrent founder mutations ', 'relation': 'have revealed ', 'condition': 'in the substrate-binding cleft of the cullin-RING ubiquitin ligase adaptor speckle-type POZ protein (SPOP) in approximately 10% of primary PC'}, {'e1': 'Genome sequencing studies ', 'e2': 'recurrent founder mutations in the substrate-binding cleft of the cullin-RING ubiquitin ligase adaptor speckle-type POZ protein (SPOP)', 'relation': 'have revealed ', 'condition': ' in approximately 10% of primary PC'}, {'e1': 'SPOP proteins harboring PC-specific mutations ', 'e2': 'defective ', 'relation': 'have been reported as being ', 'condition': 'in mediating ubiquitylation and proteasomal degradation of AR and its co-activator NCOA3'}, {'e1': 'reduced ubiquitylation ', 'e2': 'increased protein levels ', 'relation': 'that was accompanied by ', 'condition': 'in the presence of SPOP mutations.'}]"
430,P46P4,"TRIM24 has been implicated in driving different tumor types through its ability to interfere with tumor-suppressive and oncogenic pathways. Its N-terminal tripartite motifs include a RING domain, which is involved in ubiquitylation and degradation of p53. Moreover, a C-terminal tandem plant homeodomain finger-bromodomain confers TRIM24 with the ability to recognize unmodified histone H3K4 through the former domain, as well as H3K23-acetyl through the latter domain. This chromatin-interacting module has been implicated in general transcriptional co-regulation, as well as in the activation of estrogen-responsive genes in breast cancer and the PIK3CA gene in glioma. Through its conserved single LxxLL motif TRIM24 interacts with the AF-2 domain of several nuclear receptors, including AR. In line with these observations, TRIM24 was shown to enhance AR-mediated gene activation in reporter assays. Whether these different functions of TRIM24 influence PC progression is not known.","[{'e1': 'a C-terminal tandem plant homeodomain finger-bromodomain', 'e2': ' unmodified histone H3K4 ', 'relation': ' confers TRIM24 with the ability to recognize', 'condition': 'through the former domain'}, {'e1': 'a C-terminal tandem plant homeodomain finger-bromodomain', 'e2': ' H3K23-acetyl', 'relation': ' confers TRIM24 with the ability to recognize', 'condition': ' through the latter domain'}]"
431,P46P6,"In summary, we report an oncogenic role for TRIM24 as a transcriptional activator and mediator of hormone-refractory PC cell growth in SPOP mutant and CRPC. We hypothesize that our new insights will provide the rationale for targeting TRIM24 in these settings.","[{'e1': 'oncogenic role for TRIM24 ', 'e2': 'hormone-refractory PC cell growth ', 'relation': 'as a transcriptional activator and mediator of ', 'condition': 'in SPOP mutant and CRPC'}]"
432,P47P3,"Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG+, m-ETS+, m-SPINK1+ and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1+ tumors were more common in African-American men but less commonly associated with positive surgical margins compared to the m-ERG+ group. Compared to the Triple Negative group, m-SPINK1+ showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences among m-ERG+, m-ETS+ and Triple Negative cases. m-SPINK1+ independently predicted prostate cancer specific mortality after metastasis and biochemical recurrence.","[{'e1': ' m-SPINK1+ ', 'e2': 'race and surgical margins ', 'relation': 'showed similar associations with ', 'condition': 'in univariable and multivariable analyses across the entire cohort'}, {'e1': 'm-SPINK1+', 'e2': ' prostate cancer specific mortality', 'relation': ' independently predicted', 'condition': ' after metastasis and biochemical recurrence.'}]"
433,P47P4,SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome.,"[{'e1': 'SPINK1 over expression ', 'e2': 'prostate cancer specific mortality ', 'relation': 'is associated with ', 'condition': 'in at risk men with biochemical and clinical recurrence after prostatectomy'}, {'e1': 'SPINK1 over expression ', 'e2': 'prostate cancer specific mortality in at risk men with biochemical and clinical recurrence ', 'relation': 'is associated with ', 'condition': 'after prostatectomy'}]"
434,P47P6,"Transcriptome characterization has also enabled the subtyping of cases of prostate cancer on the basis of mutually exclusive molecular events, namely ERG fusions, ETS fusions, SPINK1 over expression or none of these (TripleNeg), which may aid in the assessment of tumor lineage and clinical outcomes. However, to date, studies using these molecular events to evaluate clinical outcomes have generated conflicting results and have been limited by small sample sizes, short followup or confounding by multiple treatment modalities. As a result the influence of molecular subtypes on clinical outcome heterogeneity has been inadequately studied.","[{'e1': 'Transcriptome characterization ', 'e2': 'subtyping of cases of prostate cancer ', 'relation': 'has also enabled the ', 'condition': 'on the basis of mutually exclusive molecular events'}]"
435,P47P7,"Therefore, we performed genome-wide transcriptome analysis using data generated while developing a clinically available prognostic assay on a natural history cohort of men who underwent radical prostatectomy without further treatment until the time of metastasis. We also evaluated alternative computational tools for molecular subtyping, and determined clinicopathological and clinical outcomes associations. Finally, we evaluated whether molecular subtyping changes the predictive ability of the genomic assay.","[{'e1': 'a natural history cohort of men ', 'e2': 'radical prostatectomy without further treatment ', 'relation': 'who underwent ', 'condition': 'until the time of metastasis'}]"
436,P47P8,"We evaluated the use of data generated from a clinically available prognostic assay for determining ERG, ETS and SPINK genomic aberrations. Although clinical associations between subtypes and outcomes have been adequately described, little is known about these associations in treatment-free cohorts. In a retrospective case-cohort study of NCCN intermediate and high risk patients who did not undergo adjuvant treatment after radical prostatectomy until the time of metastasis, SPINK1 expression positively correlates with prostate cancer specific mortality after biochemical recurrence and with metastatic progression. Further molecular subtyping of prostate cancer and disease stratification will be important to better identify subsets of post-radical prostatectomy patients who will benefit from adjuvant therapies.","[{'e1': 'SPINK1 expression', 'e2': 'prostate cancer specific mortality ', 'relation': ' positively correlates with ', 'condition': 'after biochemical recurrence '}]"
437,P48P3,"Characterizing the genomic landscape of metastatic prostate cancer that has progressed despite castration levels of serum testosterone, as induced by gonadotrophin-releasing hormone agonists, termed castration-resistant prostate cancer, has been even more challenging given the lack of biopsy sampling of metastases in routine clinical practice and the difficulties in obtaining quantitatively and qualitatively adequate tissue from metastatic sites, such as bone. Nevertheless, data from multiple rigorous, large, whole genome, exome and/or transcriptome sequencing studies have revolutionized our understanding of the genomic processes underlying the development and evolution of prostate cancer. For example, DNA copy-number alterations and chromosomal rearrangements, compared with point mutations or small insertion and/or deletion mutations, are more frequently observed alterations in patients with prostate cancer. Importantly, higher burdens of copy-number alterations and other mutations have been observed in patients with more aggressive prostate tumours in numerous studies, and correlate with clinical outcomes.","[{'e1': 'DNA copy-number alterations and chromosomal rearrangements ', 'e2': ' observed alterations ', 'relation': 'are more frequently', 'condition': 'in patients with prostate cancer'}]"
438,P48P4,"Despite these advances, application of these insights into clinical decision making, particularly for patients with metastatic disease, remains in its infancy and therapeutic strategies are largely driven by the presence, and extent of routine clinical and pathological factors. Over the next decade, insights from genomics are likely to have a much more prominent role in drug development, prognostication, patient selection, monitoring treatment response and/or resistance, and clinical practice as a whole. In this Review, we outline a selected number of important genomic alterations in prostate cancer, and the clinical implications of these discoveries.","[{'e1': 'insights from genomics', 'e2': 'prominent role ', 'relation': ' are likely to have a much more ', 'condition': 'in drug development'}, {'e1': 'insights from genomics', 'e2': 'prominent role ', 'relation': ' are likely to have a much more ', 'condition': 'in prognostication'}, {'e1': 'insights from genomics', 'e2': 'prominent role ', 'relation': ' are likely to have a much more ', 'condition': 'in patient selection'}, {'e1': 'insights from genomics', 'e2': 'prominent role ', 'relation': ' are likely to have a much more ', 'condition': 'in monitoring treatment response and/or resistance'}, {'e1': 'insights from genomics', 'e2': 'prominent role ', 'relation': ' are likely to have a much more ', 'condition': 'in clinical practice as a whole'}]"
439,P49P2,"The study population includes consented patients who underwent a radical retropubic prostatectomy (RP) and bilateral pelvic lymph node dissection at the University of Southern California in the PSA-era (1988–2008). We used a nested case-control study of 187 organ-confined patients (pT2N0M0): 154 with no recurrence (“controls”) and 33 with clinical recurrence (“cases”). RNA was obtained from laser capture microdissected malignant glands representative of the overall Gleason score of each patient. Whole genome gene expression profiles (29,000 transcripts) were obtained using the Whole Genome DASL HT platform (Illumina, Inc). A gene expression signature of PCa clinical recurrence was identified using stability selection with elastic net regularized logistic regression. Three existing datasets generated with the Affymetrix Human Exon 1.0ST array were used for validation: Mayo Clinic (MC, n = 545), Memorial Sloan Kettering Cancer Center (SKCC, n = 150), and Erasmus Medical Center (EMC, n = 48). The areas under the ROC curve (AUCs) were obtained using repeated fivefold cross-validation.","[{'e1': 'consented patients ', 'e2': ' a radical retropubic prostatectomy (RP) and bilateral pelvic lymph node dissection', 'relation': 'who underwent', 'condition': ' at the University of Southern California in the PSA-era'}]"
440,P49P8,"In summary, we report a 28-gene model that used in conjunction with clinical variables improves the prediction of clinical recurrence among early stage localized PCa. This model, once validated in additional external databases, may aid clinicians in identifying patients with early localized disease at high risk of recurrence who may benefit from more aggressive treatments at the time of radical prostatectomy.","[{'e1': ' patients with early localized disease at high risk of recurrence ', 'e2': 'more aggressive treatments ', 'relation': 'who may benefit from ', 'condition': 'at the time of radical prostatectomy.'}]"
441,P50P1,"TMPRSS2-ERG has been proposed to be a prognostic marker for prostate cancer. The aim of this study was to identify changes in metabolism, genes and biochemical recurrence related to TMPRSS2-ERG by using an integrated approach, combining metabolomics, transcriptomics, histopathology and clinical data in a cohort of 129 human prostate samples (41 patients). Metabolic analyses revealed lower concentrations of citrate and spermine comparing ERGhigh to ERGlow samples, suggesting an increased cancer aggressiveness of ERGhigh compared to ERGlow. These results could be validated in a separate cohort, consisting of 40 samples (40 patients), and magnetic resonance spectroscopy imaging indicated an in vivo translational potential. Alterations of gene expression levels associated with key enzymes in the metabolism of citrate and polyamines were in consistence with the metabolic results. Furthermore, the metabolic alterations between ERGhigh and ERGlow were more pronounced in low Gleason samples than in high Gleason samples, suggesting it as a potential tool for risk stratification. However, no significant difference in biochemical recurrence was detected, although a trend towards significance was detected for low Gleason samples. Using an integrated approach, this study suggests TMPRSS2-ERG as a potential risk stratification tool for inclusion of active surveillance patients.","[{'e1': 'metabolic alterations', 'e2': 'ERGhigh and ERGlow were more pronounced ', 'relation': ' between ', 'condition': 'in low Gleason samples than in high Gleason samples'}]"
442,P50P2,"The genetic fusion between the erythroblast transformation-specific transcriptional factor ETS-related gene and the androgen-responsive promotor transmembrane protease, serine 2 is suggested to be a major mechanism driving prostate carcinogenesis. The TMPRSS2-ERG gene fusion is the most common gene rearrangement in prostate cancer, with a reported prevalence of 15-78%. Presence of the gene fusion is the main reason for overexpression of ERG which is further associated with epithelial-to-mesenchymal potential, cell invasion and cell proliferation.","[{'e1': 'The TMPRSS2-ERG gene fusion', 'e2': 'gene rearrangement', 'relation': ' is the most common ', 'condition': ' in prostate cancer'}]"
443,P50P3,"From the initial discovery in 2005, the TMPRSS2-ERG gene fusion has been linked to clinical outcome parameters such as early onset of prostate cancer, negative outcome in watchful waiting patients and a higher risk of disease progression in active surveillance patients. However, considering the prognostic value of TMPRSS2-ERG in prostatectomy patients, most studies find no association to outcome after surgery. In a meta-analysis of 5,074 prostatectomy specimens, there were no associations between the presence of TMPRSS2-ERG and biochemical recurrence or lethal disease. Although the clinical significance of TMPRSS2-ERG is yet to be proven, presence of the fusion gene is a key genomic event specific for prostate cancer that may be of importance for risk assessment or treatment stratification of prostate cancer patients.","[{'e1': ' TMPRSS2-ERG gene fusion ', 'e2': 'disease progression ', 'relation': 'has been linked to higher risk of ', 'condition': 'in active surveillance patients'}]"
444,P50P6,"This study presents a distinct metabolic profile with concordant alterations of gene expression levels of key metabolic enzymes in prostate tissue samples with the presence of TMPRSS2-ERG. The metabolic profile was especially connected to the metabolism of polyamines and citrate, but also glycolysis and fatty acid metabolism. Our results indicate that TMPRSS2-ERG differentiates towards a phenotype that is associated with characteristics of an aggressive phenotype of prostate cancer. Additionally, the observed metabolic alterations can be translated to in vivo patient MRSI.","[{'e1': 'distinct metabolic profile ', 'e2': 'key metabolic enzymes ', 'relation': 'with concordant alterations of gene expression levels of ', 'condition': 'in prostate tissue samples with the presence of TMPRSS2-ERG'}]"
445,P52P1,Aside from Gleason sum few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential.,"[{'e1': 'few factors ', 'e2': 'prostate cancer patients ', 'relation': 'accurately identify the subset of ', 'condition': 'at high risk for metastatic progression'}]"
446,P53P4,"To gain insight into the cellular factors controlling AR activity and potentially CRPC, we performed an unbiased, genome-wide siRNA screen for factors that reduced AR activity upon depletion using a Drosophila cell system. This was followed by functional analyses of homologous factors in human prostate cancer cells, revealing several new factors that regulate AR activity and prostate cancer cell proliferation.","[{'e1': 'an unbiased, genome-wide siRNA screen', 'e2': 'AR activity ', 'relation': ' for factors that reduced ', 'condition': 'upon depletion using a Drosophila cell system'}]"
447,P54P1,"Developmental exposure to endocrine-disrupting chemicals (EDCs), 17β-estradiol-3-benzoate (EB) and bisphenol A (BPA), increases susceptibility to prostate cancer (PCa) in rodent models. Here, we used the methylated-CpG island recovery assay (MIRA)-assisted genomic tiling and CpG island arrays to identify treatment-associated methylome changes in the postnatal day (PND)90 dorsal prostate tissues of Sprague-Dawley rats neonatally (PND1, 3, and 5) treated with 25 μg/pup or 2,500 μg EB/kg body weight (BW) or 0.1 μg BPA/pup or 10 μg BPA/kg BW. We identified 111 EB-associated and 86 BPA-associated genes, with 20 in common, that have significant differentially methylated regions. Pathway analysis revealed cancer as the top common disease pathway. Bisulfite sequencing validated the differential methylation patterns observed by array analysis in 15 identified candidate genes. The methylation status of 7 (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, Creb3l4) of these 15 genes exhibited an inverse correlation with gene expression in tissue samples. Cell-based assays, using 5-aza-cytidine-treated normal (NbE-1) and cancerous (AIT) rat prostate cells, added evidence of DNA methylation-mediated gene expression of 6 genes (exception: Paqr4). Functional connectivity of these genes was linked to embryonic stem cell pluripotency. Furthermore, clustering analyses using the dataset from The Cancer Genome Atlas revealed that expression of this set of 7 genes was associated with recurrence-free survival of PCa patients. In conclusion, our study reveals that gene-specific promoter methylation changes, resulting from early-life EDC exposure in the rat, may serve as predictive epigenetic biomarkers of PCa recurrence, and raises the possibility that such exposure may impact human disease.","[{'e1': 'Developmental exposure to endocrine-disrupting chemicals (EDCs), 17β-estradiol-3-benzoate (EB) and bisphenol A (BPA)', 'e2': 'prostate cancer (PCa) ', 'relation': 'increases susceptibility to ', 'condition': 'in rodent models'}, {'e1': ' methylated-CpG island recovery assay (MIRA)-assisted genomic tiling and CpG island arrays ', 'e2': 'treatment-associated methylome changes ', 'relation': 'to identify ', 'condition': 'in the postnatal day (PND)90 dorsal prostate tissues of Sprague-Dawley rats neonatally '}, {'e1': 'Bisulfite sequencing ', 'e2': 'differential methylation patterns observed by array analysis ', 'relation': 'validated the ', 'condition': 'in 15 identified candidate genes'}, {'e1': 'The methylation status of 7 (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, Creb3l4) of these 15 genes ', 'e2': ' gene expression ', 'relation': 'exhibited an inverse correlation with', 'condition': 'in tissue samples'}]"
448,P54P2,"Exposure to environmental agents is a risk factor for multiple diseases. Evidence is mounting in support of the causal link between exposure to xenoestrogens and human diseases, including cancer. Bisphenol A (BPA) is a ubiquitous environmental xenoestrogen widely used during the production of polycarbonate plastics, epoxy resins, carbonless receipt paper, and hundreds of other manufactured products. The fact that urinary BPA is detectable in more than 95% of the US population indicates that BPA readily leaches into the environment, contaminates our food and water, and enters our bodies. Chronic exposure to BPA in rodents and in humans is associated with prostate cancer (PCa) and its pre-lesions. Moreover, BPA is detectable in umbilical cord blood and sera of newborns, which elevates the concern of early-life BPA exposure and development of later-life disease. As an endocrine-disrupting chemical (EDC), BPA binds to estrogen receptors (ERs) ESR1, ESR2, and GPER1, which are expressed in the rodent and human prostate epithelial cells. While affinity for nuclear ERs is low compared to estradiol-17β, BPA has equivalent activational capacities for membrane ERs and rapid actions of low-dose BPA have been documented in prostate cells. Finally, BPA can also signal through non-ER pathways.","[{'e1': 'Chronic exposure to BPA ', 'e2': 'prostate cancer (PCa) and its pre-lesions', 'relation': 'is associated with ', 'condition': 'in rodents '}, {'e1': 'Chronic exposure to BPA ', 'e2': 'prostate cancer (PCa) and its pre-lesions', 'relation': 'is associated with ', 'condition': 'in humans'}]"
449,P54P3,"Like BPA, 17β-estradiol-3-benzoate (EB) is a ubiquitous environmental agent. It is an estradiol analog commonly used in livestock for inducing weight gain and synchronizing estrus cycles in heifers and cattle. Since EB binds ERs with high affinity, unintended exposures may trigger estrogenic responses that compromise health. In rodents, neonatal EB exposure (30–125 ng/day in mouse and 125–500 ng/day in rats) has been shown to induce the production of morphologically abnormal sperm during adulthood. Similarly, rats neonatally exposed to 25 μg EB developed prostates with a greater risk of malignant changes with aging, including severe prostatic intraepithelial neoplasia (PIN), a precancerous condition. Since production of morphologically abnormal sperm and induction of increased susceptibility to hormonal carcinogenesis are similarly observed following neonatal BPA exposure, these findings strongly implicate early life as a susceptible window for environmental xenoestrogens to predispose later-life disease risk and EB can serve as a positive estrogen control in studies of weaker estrogenic agents such as BPA. While emerging evidence indicates that epigenetic modifications are involved, the molecular underpinnings of this process remain to be fully clarified.","[{'e1': '17β-estradiol-3-benzoate (EB) ', 'e2': ' weight gain and synchronizing estrus cycles ', 'relation': 'is an estradiol analog commonly used in livestock for inducing', 'condition': 'in heifers and cattle'}, {'e1': ' neonatal EB exposure', 'e2': ' the production of morphologically abnormal sperm ', 'relation': ' has been shown to induce', 'condition': ' during adulthood in rodents'}, {'e1': ' production of morphologically abnormal sperm ', 'e2': 'hormonal carcinogenesis are similarly observed ', 'relation': 'and induction of increased susceptibility to ', 'condition': 'following neonatal BPA exposure'}]"
450,P54P4,"To initially interrogate whether neonatal exposure to EB and BPA reprogrammed the prostate epigenome, we exposed rats to an environmentally relevant dose of BPA (10 μg/kg body weight) or EB (2,500 μg/kg BW) on postnatal days 1, 3, and 5. We observed that this transient developmental exposure increased the dorsal and lateral prostate lobe susceptibility to adult-onset E2-induced carcinogenesis, markedly augmenting the incidence and severity of lesions as compared to oil-treated controls. Using methylation-sensitive restriction fingerprinting to identify altered DNA methylation marks, we found that neonatal EB and BPA exposures were associated with the dysregulation of phosphodiesterase type IV variant 4 (Pde4d4), hippocalcin-like 1 (Hpcal1; also known as visinin-like protein-3, Vilip-3), and high mobility group nucleosome binding domain 5 (Hmgn5; formerly known as nucleosome binding protein 1, Nsbp1) through aberrant promoter methylation detected on postnatal day (PND)10, 90, and 200. Together, these findings provided the first evidence that early-life environmental exposure to EDC reprogrammed the prostate epigenome and identified a developmental basis of PCa risk with aging. Moreover, the expression of DNA methylation transferase 3a and 3b (Dnmt3a and Dnmt3b) and methyl-CpG binding domain protein 2 and 4 (Mbd2 and Mbd4) was upregulated in PND10 and 90 prostate tissues, providing a mechanistic basis for reprogramming of DNA methylation marks upon early-life EDC exposure. Thus, we propose that differential methylation of genes that persist in the PND90 prostate primes the tissue for heightened sensitivity to a secondary exposure to rising estradiol later in life, as occurs in aging males. This is particularly relevant since elevated estrogens have been associated with increased PCa risk in men and are sufficient to transform the human prostate epithelium.","[{'e1': 'rats exposed', 'e2': 'BPA (10 μg/kg body weight) or EB (2,500 μg/kg BW) ', 'relation': 'to an environmentally relevant dose of ', 'condition': 'on postnatal days 1, 3, and 5'}, {'e1': 'neonatal EB and BPA exposures ', 'e2': 'the dysregulation of phosphodiesterase type IV variant 4 (Pde4d4)', 'relation': 'were associated with ', 'condition': 'through aberrant promoter methylation detected on postnatal day (PND)10, 90, and 200'}, {'e1': 'neonatal EB and BPA exposures ', 'e2': 'hippocalcin-like 1 (Hpcal1; also known as visinin-like protein-3, Vilip-3)', 'relation': 'were associated with ', 'condition': 'through aberrant promoter methylation detected on postnatal day (PND)10, 90, and 200'}, {'e1': 'neonatal EB and BPA exposures ', 'e2': ' high mobility group nucleosome binding domain 5 (Hmgn5; formerly known as nucleosome binding protein 1, Nsbp1) ', 'relation': 'were associated with ', 'condition': 'through aberrant promoter methylation detected on postnatal day (PND)10, 90, and 200'}, {'e1': 'a mechanistic basis ', 'e2': ' DNA methylation marks ', 'relation': 'for reprogramming of', 'condition': 'upon early-life EDC exposure'}, {'e1': 'elevated estrogens ', 'e2': 'increased PCa risk ', 'relation': 'have been associated with ', 'condition': 'in men'}]"
451,P54P5,"While these findings had a major impact on the field of EDC research and developmental basis of carcinogenesis, a genome-wide search for additional DNA methylation targets of neonatal exposure to xenoestrogens is warranted for an unbiased discovery of other epigenetic marks that may underlie increased PCa risk with aging. To accomplish this goal, we herein used the methylated-CpG island recovery assay (MIRA)-assisted genomic tiling and CpG island array analysis and identified distinct and common EB-/BPA-associated genes in PND90 prostate tissues from rats with neonatal exposure to these xenoestrogens. Among 25 epigenetically regulated candidate genes, the promoter methylation status of 7 genes (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, Creb3l4) was inversely correlated to gene expression. These validated genes have functional connectivity associated with stem cell pluripotency. Of clinical relevance, expression of these genes was found to be associated with recurrence-free survival of 497 patients in The Cancer Genome Atlas (TCGA) PCa cohort, suggesting that they may have utilities for predicting disease progression and patient stratification based on disease aggressiveness.","[{'e1': 'expression of these genes', 'e2': 'recurrence-free survival of 497 patients ', 'relation': ' was found to be associated with ', 'condition': 'in The Cancer Genome Atlas (TCGA) PCa cohort'}]"
452,P54P6,"In summary, we have identified a set of 7 genes (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, and Creb3l4) with differential methylation at the promoter region, in PND90 dorsal prostate tissue of rats neonatally exposed to EDCs. The methylation pattern of these 7 genes was inversely correlated to gene expression. Cell-based studies using 5-aza-cytidine-treated normal (NbE-1) and cancerous (AIT) prostate epithelial cell lines further confirmed that gene expression was regulated by DNA methylation, in 6 of the 7 genes. To provide clinical relevance, 4 of the 7 genes (PITX3, WNT10B, PAQR4, and TPD52) have been reported to be differentially methylated between PCa and normal adjacent tissues. Moreover, expression of the 7 genes is associated with the recurrence-free survival of PCa patients. Taken together, we conclude that DNA methylation changes in our novel 7-gene signature may be an epigenetic signature associated with increased cancer susceptibility in the adult gland due to early-life exposure.","[{'e1': 'a set of 7 genes (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, and Creb3l4) ', 'e2': 'the promoter region', 'relation': 'with differential methylation at ', 'condition': 'in PND90 dorsal prostate tissue of rats neonatally exposed to EDCs'}, {'e1': ' gene expression ', 'e2': 'DNA methylation', 'relation': 'was regulated by ', 'condition': 'in 6 of the 7 genes.'}, {'e1': ' DNA methylation changes in our novel 7-gene signature may be an epigenetic signature ', 'e2': ' increased cancer susceptibility ', 'relation': 'associated with', 'condition': 'in the adult gland due to early-life exposure.'}]"
453,P55P2,"Breast cancer is the second leading cause of cancer death in Western countries and the most frequently diagnosed cancer in Western women. A family history of breast cancer is a major risk factor for developing breast cancer. Approximately 10–15% of breast cancer patients have at least one first-degree relative with breast cancer. Depending on the number of affected first-degree relatives, this implies risk ratios for breast cancer of 1.80 for one affected relative to 3.90 for three or more affected relatives.","[{'e1': 'Breast cancer ', 'e2': 'cancer death ', 'relation': 'is the second leading cause of ', 'condition': 'in Western countries '}, {'e1': 'Breast cancer ', 'e2': ' diagnosed cancer ', 'relation': 'is the most frequently', 'condition': 'in Western women'}]"
454,P55P3,"Familial breast cancer has been associated with mutations in several high- and moderate-risk breast cancer susceptibility genes, as well as an increasing number of low-risk breast cancer susceptibility alleles. The two high-risk genes BRCA1 and BRCA2 were identified in the 1990s and germline mutations in these genes confer average cumulative lifetime breast cancer risks by age 70 of 65% and 45%, respectively. Mutations in moderate-risk genes ATM, CHEK2, PALB2, and RAD50 confer 2- to 4-fold increased breast cancer risks, although recent evidence suggests that the breast cancer risk conferred by PALB2 mutations may be higher than initially thought. The more than 90 identified common low-risk alleles, on the other hand, display small effect sizes of up to 1.3. However, taken together in a polygenic risk score calculated from 77 SNPs, the lifetime risk of breast cancer for women in the highest quantile of this polygenic risk score was 17%. In total, these breast cancer susceptibility genes and alleles account for approximately 35% of the familial breast cancer risk, which means that the underlying cause of the majority of the familial breast cancer risk thus still remains unexplained.","[{'e1': 'Familial breast cancer', 'e2': 'mutations ', 'relation': ' has been associated with ', 'condition': 'in several high- and moderate-risk breast cancer susceptibility genes'}, {'e1': 'Familial breast cancer', 'e2': 'mutations ', 'relation': ' has been associated with ', 'condition': 'in an increasing number of low-risk breast cancer susceptibility alleles.'}]"
455,P55P4,"In this respect, the rare variant c.251G>A (p.G84E) in the HOXB13 gene was reported to be associated with prostate cancer. Meta-analyses have estimated the increased prostate cancer risk from this mutation to be 4- to 5-fold and even higher among early onset prostate cancer patients and prostate cancer patients with a family history of prostate cancer. Moreover, fine-scale mapping at the HOXB gene cluster at 17q21–22 had identified a number of highly correlated common SNPs that were associated with prostate cancer risk and tagging the rare HOXB13 p.G84E variant. This not only further established the association between HOXB13 p.G84E and prostate cancer risk, but also provided evidence that genome-wide association study associations could actually be driven by rare variants. Interestingly, the HOXB13 gene encodes a transcription factor that plays an important regulatory role during embryonic development, but also in tumorigenesis. For example, HOXB13 was reported to regulate the transcription of androgen receptor target genes and together with HOXA9, HOXB13 is the most commonly deregulated gene in solid cancers. Moreover, HOXB13 was shown to preferentially bind a low-risk prostate cancer susceptibility allele located in an androgen receptor and FOXA1 binding site, thereby enhancing RFX6 expression and promoting metastasis. In breast cancer, HOXB13 gene expression is regulated by estrogen in an estrogen receptor dependent manner. Furthermore, a high HOXB13:IL17BR expression ratio was found to be a prognostic and predictive biomarker for estrogen receptor-positive breast cancer patients. The poor response to tamoxifen therapy that is predicted from high HOXB13 expression has been shown to be mediated by HOXB13 through the direct suppression of estrogen receptor, the induction of IL6 expression and mTOR pathway activation. Considering these observations, HOXB13 might also be a likely candidate for being a breast cancer susceptibility gene. So far, three studies have investigated this hypothesis but obtained contradictory results. In the study by Alanee et al., the HOXB13 p.G84E mutation was shown to confer an increased breast cancer risk, however, Akbari et al. could not replicate this association in a larger study. Laitinen et al. also found no association with breast cancer risk, but did observe a suggestive association in a particular high-risk subgroup. Importantly, all three studies only investigated the prostate cancer risk-associated variant p.G84E.","[{'e1': 'the rare variant c.251G>A (p.G84E) ', 'e2': 'with prostate cancer', 'relation': 'was reported to be associated ', 'condition': 'in the HOXB13 gene'}, {'e1': 'the HOXB13 gene ', 'e2': ' important regulatory role ', 'relation': 'encodes a transcription factor that plays an', 'condition': 'during embryonic development'}, {'e1': 'the HOXB13 gene ', 'e2': ' important regulatory role ', 'relation': 'encodes a transcription factor that plays an', 'condition': ' in tumorigenesis'}, {'e1': 'HOXB13 ', 'e2': ' deregulated gene ', 'relation': 'is the most commonly', 'condition': 'in solid cancers'}, {'e1': 'HOXB13 ', 'e2': 'a low-risk prostate cancer susceptibility allele ', 'relation': 'preferentially binds ', 'condition': 'located in an androgen receptor '}, {'e1': 'HOXB13 ', 'e2': 'a low-risk prostate cancer susceptibility allele ', 'relation': 'preferentially binds ', 'condition': 'located in FOXA1 binding site'}, {'e1': ' HOXB13 gene expression ', 'e2': 'estrogen ', 'relation': 'is regulated by ', 'condition': ' In breast cancer'}, {'e1': ' HOXB13 gene expression ', 'e2': 'estrogen ', 'relation': 'is regulated by ', 'condition': 'in an estrogen receptor dependent manner'}, {'e1': 'The poor response to tamoxifen therapy', 'e2': 'HOXB13', 'relation': ' has been shown to be mediated by ', 'condition': ' through the direct suppression of estrogen receptor'}, {'e1': 'The poor response to tamoxifen therapy', 'e2': 'HOXB13', 'relation': ' has been shown to be mediated by ', 'condition': 'through the induction of IL6 expression '}, {'e1': 'The poor response to tamoxifen therapy', 'e2': 'HOXB13', 'relation': ' has been shown to be mediated by ', 'condition': 'through mTOR pathway activation'}]"
456,P56P10,"Therefore, we postulated that THOR is hypermethylated in most cancers. In prostate cancer THOR demonstrated the diagnostic ability to differentiate cancer from normal prostate tissue and to discriminate indolent from aggressive PCa. Furthermore, THOR might be used as a marker to predict patient outcome in addition to other currently used markers.","[{'e1': ' THOR ', 'e2': 'cancer from normal prostate tissue ', 'relation': 'demonstrated the diagnostic ability to differentiate ', 'condition': ' In prostate cancer'}, {'e1': ' THOR ', 'e2': ' indolent from aggressive PCa', 'relation': 'demonstrated the diagnostic ability to discriminate', 'condition': ' In prostate cancer'}]"
457,P56P11,"In the era of precision medicine where the aim is to determine patient-specific outcome, THOR hypermethylation represents a potential candidate biomarker for cancer diagnostics in biopsies. It can also determine aggressiveness of tumors with similar histological grade and be used as a companion biomarker for therapies using telomerase inhibitors or demethylating enzymes.","[{'e1': ' THOR hypermethylation ', 'e2': 'potential candidate biomarker for cancer diagnostics ', 'relation': 'represents a ', 'condition': 'in biopsies'}]"
458,P56P12,"Finally, combining THOR with other biomarkers such as PSA can identify the patients with extremely low risk of recurrence where surveillance protocols could be applied. Further studies are required to verify if THOR methylation can change the current treatment paradigms in low or intermediate risk PCa.","[{'e1': 'THOR methylation ', 'e2': 'current treatment paradigms ', 'relation': 'can change the ', 'condition': 'in low or intermediate risk PCa.'}]"
459,P56P2,We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.,"[{'e1': 'Methylation status of the whole TERT gene ', 'e2': 'MeDIP-Seq', 'relation': 'was determined by ', 'condition': 'in benign and malignant prostate samples '}, {'e1': 'The prognostic role of THOR ', 'e2': 'pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.', 'relation': ' was assessed by ', 'condition': 'in PCa'}]"
460,P56P4,"Prostate cancer (PCa) is the most frequently diagnosed cancer and the second most common cause of cancer-related mortality among men. Although one sixth of men will be diagnosed with PCa during their lifetime, only one in thirty six will die from this disease.","[{'e1': 'Prostate cancer (PCa) ', 'e2': 'diagnosed cancer ', 'relation': 'is the most frequently ', 'condition': 'among men'}, {'e1': 'Prostate cancer (PCa) ', 'e2': 'cancer-related mortality', 'relation': 'is second most common cause of ', 'condition': 'among men'}]"
461,P56P8,"Cancer cells achieve limitless self-renewal capacity through the activation of telomere maintenance mainly through activation of telomerase which provides immortalization for 90% of cancers. The catalytic subunit of the telomerase complex is termed Telomerase Reverse Transcriptase (TERT) and its expression has been observed in most malignant cancers including PCa. Telomere shortening and telomere length has been shown to act as a predictor of disease progression in PCa. Moreover, telomerase activation stabilizes shorter telomeres and is a putative early marker for prostate carcinogenesis. Analysis of telomerase activity and TERT expression require high quality RNA and cell extracts that are challenging, especially when paraffin embedded tissues are considered. Therefore, a DNA based assay that correlates with telomerase activity would be extremely useful as a diagnostic and prognostic tool in cancer.","[{'e1': 'Telomere shortening ', 'e2': 'predictor of disease progression ', 'relation': ' has been shown to act as a ', 'condition': 'in PCa'}, {'e1': 'telomere length', 'e2': 'predictor of disease progression ', 'relation': ' has been shown to act as a ', 'condition': 'in PCa'}, {'e1': 'a DNA based assay that correlates with telomerase activity ', 'e2': 'a diagnostic and prognostic tool ', 'relation': 'would be extremely useful as ', 'condition': 'in cancer.'}]"
462,P56P9,"Epigenetic gene regulation through DNA methylation has been associated with diagnosis and prognosis in multiple cancers including brain and prostate cancer. We recently identified a specific area in the TERT promoter, termed THOR (TERT Hypermethylated Oncological Region), which is hypermethylated only in cancers expressing TERT and non-hypermethylated in normal tissues and low-grade pediatric tumors, which do not express TERT. THOR predicted outcome and tumor progression in several subgroups of pediatric cancers.","[{'e1': 'Epigenetic gene regulation through DNA methylation', 'e2': 'diagnosis and prognosis ', 'relation': ' has been associated with ', 'condition': 'in multiple cancers including brain and prostate cancer'}, {'e1': 'THOR ', 'e2': 'outcome and tumor progression ', 'relation': 'predicted ', 'condition': 'in several subgroups of pediatric cancers.'}]"
463,P57P1,"The CXCR4/CXCL12 axis plays a central role in systemic metastasis of prostate carcinoma (PCa), thereby representing a promising target for future therapies. Recent data suggest that the CXCR4/CXCL12 axis is functionally linked to the PD-1/PD-L1 immune checkpoint. We evaluated the prognostic value of aberrant CXCL12 DNA methylation with respect to PD-L1 expression in primary PCa.","[{'e1': 'the prognostic value of aberrant CXCL12 DNA methylation ', 'e2': 'PD-L1 expression ', 'relation': 'with respect to ', 'condition': 'in primary PCa.'}]"
464,P57P10,"Immunotherapy has been emerging as a promising treatment strategy in cancer patients. Among major immune checkpoints, e.g. PD-1 and CTLA4, the pharmacologic blockage of CXCR4 and its endogenous ligand CXCL12 has appeared as a prime target for blocking strategies in the treatment of cancer patients. Recent studies have focused on pharmacological CXCR4 inhibition within the cross relation of anti-PD-1/anti-PD-L1 drug resistance. In vitro and murine in vivo studies have provided data that ADM3100 induced blockage of CXCR4 restores sensitivity to PD-1 and CTLA-4 checkpoint inhibitors in anti-PD1 and anti-CTLA-4 drug-resistant tumors and thus might help to overcome resistance to immune therapy. Consequently, a combined anti-CXCR4/CXCL12 and anti-PD1/PD-L1 therapy is under clinical investigation in metastatic solid tumors. In our study, patients with high PD-L1 expression and aberrant CXCL12 methylation presented with significantly shorter BRC-free survival intervals than patients with either low PD-L1 expression or high PD-L1 expression plus normal CXCL12 methylation. Accordingly, a combined anti-PD-L1/PD and antagonistic CXCR4/CXCL12 treatment seems to be a promising approach in PCa as well. For the identification of eligible patients, methylation of CXCL12 together with immunohistochemical staining of PD-L1 might be a powerful tool. Whether carcinomatous CXCL12 methylation predicts responsiveness to therapeutic intervention targeting the CXCR4/CXCL12 axis remains the object of future research.","[{'e1': 'Immunotherapy ', 'e2': 'a promising treatment strategy ', 'relation': 'has been emerging as ', 'condition': 'in cancer patients'}, {'e1': 'the pharmacologic blockage of CXCR4 and its endogenous ligand CXCL12 ', 'e2': 'a prime target for blocking strategies ', 'relation': 'has appeared as ', 'condition': 'in the treatment of cancer patients'}, {'e1': 'ADM3100 induced blockage of CXCR4 ', 'e2': 'PD-1 and CTLA-4 checkpoint inhibitors ', 'relation': 'restores sensitivity to ', 'condition': 'in anti-PD1 tumors '}, {'e1': 'ADM3100 induced blockage of CXCR4 ', 'e2': 'PD-1 and CTLA-4 checkpoint inhibitors ', 'relation': 'restores sensitivity to ', 'condition': 'in anti-CTLA-4 drug-resistant tumors '}]"
465,P57P3,"CXCL12 methylation was determined by means of a methylation specific quantitative PCR analysis in a radical prostatectomy patient cohort (n = 247, training cohort). Data published by The Cancer Genome Atlas served as a testing cohort (n = 498). CXCL12 methylation results were correlated to clinicopathological parameters including biochemical recurrence (BCR)-free survival.","[{'e1': 'CXCL12 methylation ', 'e2': 'means of a methylation specific quantitative PCR analysis ', 'relation': 'was determined by ', 'condition': 'in a radical prostatectomy patient cohort'}]"
466,P57P4,CXCL12 methylation is a powerful prognostic biomarker for BCR in PCa patients after radical prostatectomy. Further studies need to ascertain if CXCL12 methylation may aid in planning active surveillance strategies.,"[{'e1': 'CXCL12 methylation ', 'e2': ' BCR ', 'relation': 'is a powerful prognostic biomarker for', 'condition': 'in PCa patients after radical prostatectomy'}, {'e1': 'CXCL12 methylation ', 'e2': 'BCR in PCa patients ', 'relation': 'is a powerful prognostic biomarker for', 'condition': 'after radical prostatectomy'}]"
467,P57P7,"Originally, CXCL12 was found to control hematopoietic cell trafficking and guide the homing of stem cells within the bone marrow. Thereby, cells with CXCR4 expression migrate towards compartments with high CXCL12 production. In the bone marrow, CXCL12 signals lead to cell chemotaxis until they are terminated through CXCR4 receptor internalization. In the long-run, steady CXCL12 binding causes CXCR4 desensitization resulting in a resting, non-deploying state of hematopoietic stem cells and tumor cells, likewise. This implies that a microenvironment with a constant CXCL12 production induces a down-regulation of CXCR4 and thereby antagonizes the process of metastasis. Gene methylation adds to the major regulatory alterations interfering with CXCL12 homeostasis in tumor epithelium, leading to a silenced CXCL12 signal in various human malignant tumors.","[{'e1': 'CXCL12 ', 'e2': 'hematopoietic cell trafficking ', 'relation': 'was found to control ', 'condition': 'within the bone marrow'}, {'e1': 'CXCL12 ', 'e2': 'guide the homing of stem cells ', 'relation': 'was found to control ', 'condition': 'within the bone marrow'}, {'e1': 'CXCL12 signals ', 'e2': 'cell chemotaxis until they are terminated ', 'relation': 'lead to ', 'condition': 'through CXCR4 receptor internalization'}, {'e1': ' Gene methylation', 'e2': 'the major regulatory alterations interfering with CXCL12 homeostasis ', 'relation': ' adds to ', 'condition': 'in tumor epithelium'}, {'e1': 'the major regulatory alterations interfering with CXCL12 homeostasis in tumor epithelium', 'e2': 'silenced CXCL12 signal ', 'relation': 'leads to a ', 'condition': 'in various human malignant tumors.'}]"
468,P57P8,"Moreover, the CXCR4/CXCL12 axis seems to be tightly linked to the immune checkpoint regulator programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) that co-operate to suppress anti-cancer immunity. In the clinical setting, anti-PD-1 and anti-PD-L1 antibodies have shown promising outcomes in cancer patients. However, a subset of patients fails to respond to checkpoint inhibition. Feig et al. recently managed to overcome anti-PD-L1 drug resistance in a murine pancreatic adenocarcinoma model by blocking CXCR4. These findings motivated us to investigate the CXCR4/CXCL12 axis within the cross-relation to PD-L1 expression in PCa.","[{'e1': 'Feig et al.', 'e2': 'anti-PD-L1 drug resistance ', 'relation': ' managed to overcome ', 'condition': 'in a murine pancreatic adenocarcinoma model by blocking CXCR4'}, {'e1': 'the CXCR4/CXCL12 axis ', 'e2': ' PD-L1 expression ', 'relation': 'within the cross-relation to', 'condition': 'in PCa.'}]"
469,P57P9,"The fact that the cohort is based on radical prostatectomy specimens, however, is a major limitation of this study. Gene methylation can be robustly determined even in little formalin-fixed pathological material. If the prognostic value of CXCL12 methylation can be transferred to a biopsy-based cohort, its analysis may be a promising tool in order to identify patients with innocuous tumors that can safely be followed by active surveillance protocols. Conversely, aberrant methylation of CXCL12 may indicate a high metastatic potential. In consequence, affected patients possibly will benefit from radical treatment, including radical prostatectomy. In a paired analysis of CXCL12 methylation based on biopsy and matched ectomy specimens, we were able to show that the results of mCXCL12 assessments are concordant. In addition, our assay seems to be able to reliably determine CXCL12 methylation in biopsy material. The variation coefficients of our results were slightly higher the lower the amount of applied DNA was, however, in homoscedastic testing, no difference could be observed. In practice, growing variances in small samples may easily be counteracted by increasing the number of replicates in the analysis. If the assay will be established for future routine use, a broad spectrum of biopsy material will be needed to precisely set the measuring range and achieve tight tolerances.","[{'e1': ' our assay', 'e2': ' CXCL12 methylation ', 'relation': ' seems to be able to reliably determine', 'condition': 'in biopsy material'}, {'e1': 'growing variances in small samples', 'e2': 'number of replicates ', 'relation': ' may easily be counteracted by increasing the ', 'condition': 'in the analysis'}]"
470,P58P1,"Patients with prostate cancer (PCa) have a variable prognosis. It is challenging to recognize the progressive disease. In this study, we focused on TSPAN1, a new member of the tetraspanin family. Its expression was decreased in progressive PCa and was an independent prognosis factor of biochemical recurrence after radical prostatectomy. In vitro, knockdown and overexpression of TSPAN1 in PCa cell lines showed that TSPAN1 could inhibit cell proliferation and migration. TSPAN1 was positive related to PTEN in both clinical specimen and mouse models. The combination of these two markers could increase their prognosis value especially in low risk patients. In vitro TSPAN1 knockdown resulted in increased Akt phosphorylation and caused evident cell cycle transition from G1 to S phase. Our data suggests that TSPAN1 is a valuable marker to recognize more progressive PCa.","[{'e1': 'TSPAN1', 'e2': 'of biochemical recurrence ', 'relation': 'was an independent prognosis factor ', 'condition': 'after radical prostatectomy'}, {'e1': 'TSPAN1', 'e2': 'PTEN ', 'relation': ' was positive related to ', 'condition': 'in clinical specimen '}, {'e1': 'TSPAN1', 'e2': 'PTEN ', 'relation': ' was positive related to ', 'condition': 'in mouse models'}, {'e1': ' The combination of these two markers ', 'e2': ' their prognosis value ', 'relation': 'could increase', 'condition': 'especially in low risk patients'}]"
471,P58P3,"Tetraspanins are a heterogeneous group of four transmembrane proteins, which are expressed across evolution from sponges to mammals. Studies have established that they can affect tumor metastasis by forming tetraspanin-enriched membrane micro-domains (TEMs) with other tetraspanins and with a variety of trans-membrane and cytosolic proteins through different mechanisms. For example, CD82 is recognized as a typical metastasis suppressor. It can interact with integrin and then form a protein complex with c-Met. Through the recruitment of regulation cofactors, CD82 influences the protein complex function, which results in promoting matrix adhesion and inducing senescence. On the other hand, CD151 and tetraspanin8 are shown to promote metastasis by supporting cell motility. The controversial role of tetraspanins in tumor progression may be due to their function of serving as a scaffold to interact with various proteins.","[{'e1': 'Tetraspanins', 'e2': 'tumor metastasis ', 'relation': 'can affect ', 'condition': 'by forming tetraspanin-enriched membrane micro-domains (TEMs) with other tetraspanins '}]"
472,P58P4,"TSPAN1 is a novel member of the tetraspanin family, and its role in tumor progression is not entirely understood. Studies in gastric, colonic, and cervical cancer have shown that TSPAN1 can promote tumor cell proliferation and invasion in vitro and its expression is elevated in these primary tumor tissues of human. However, in breast cancer it is reported that although TSPAN1 gene is amplified in most non-metastasis primary lesions, it is more likely to be obliterated in metastasis matched primary lesions. Thus, TSPAN1 has a clinical potential in distinguishing more progressive patients after operation or biopsy. To our knowledge, TSPAN1 expression panel in prostate cancer was still unreported, and all of the researches above didn’t show possible mechanisms of TSPAN1. Therefore, we decided to investigate clinical significance of TSPAN1 in our postoperative prostate cancer cohort and attempted to explore its function.","[{'e1': 'TSPAN1 gene ', 'e2': 'obliterated ', 'relation': 'is more likely to be ', 'condition': 'in metastasis matched primary lesions'}, {'e1': 'TSPAN1 ', 'e2': ' distinguishing more progressive patients', 'relation': 'has a clinical potential in', 'condition': ' after operation or biopsy'}]"
473,P58P5,"In this study, we first proved that TSPAN1 knockdown increased the phosphorylation level of Akt in vitro and changed cell cycle from phase G1 to S. PI3K/Akt pathway was one of the most prominent alternate pathways in prostate cancer. It may induce disease progression through the activation of downstream growth and survival pathways, which could be reflected as cell cycle changes and apoptosis inhibition. Another method of PI3K/Akt pathway activation in tumors was losing of its suppressor, PTEN. The PTEN gene on chromosome 10q23.3 was the most commonly deleted gene in prostate cancer. Studies have proved that PTEN loss was independently associated with increased risk of lethal progression. According to our data, TSPAN1 expression was positive related to PTEN in both patients’ specimen and mouse model. What’s more, on the basis of PTEN classification, TSPAN1 could enhance the prognosis value of PTEN in prostate cancer patients, especially in clinical low risk groups. Among these patients, PTEN alone didn’t have a significant prognosis value.","[{'e1': 'TSPAN1 expression ', 'e2': 'PTEN ', 'relation': 'was positive related to ', 'condition': 'in both patients’ specimen and mouse model'}, {'e1': 'TSPAN1 ', 'e2': ' PTEN ', 'relation': 'could enhance the prognosis value of', 'condition': 'in prostate cancer patients, especially in clinical low risk groups'}]"
474,P58P6,"The study also had limitations. Due to the limitation of follow up time, biochemical recurrence was the only analyzable end point of our cohort right now. Our cohort excluded patients received postoperative adjuvant treatment in order to exclude the interference with BFS from postoperative intervention. As a result, our cohort had a low percentage of high-risk patients, especially the patients with adverse pathology events. We believed the small number might be the reason causing no significant associations between adverse pathology and BCR. And our negative results does not necessarily mean there were no associations for TSPAN1 with APEs, Gleason score, and PSA. In conclusion, decreased expression of TSPAN1 in prostate cancer led to increased cell proliferation and migration, plausibly through the activation of PI3K/Akt pathway. Also, TSPAN1 was an independent prognosis factor of biochemical recurrence after radical prostatectomy and might have practical value especially in clinical low risk patients.","[{'e1': 'decreased expression of TSPAN1 ', 'e2': 'increased cell proliferation and migration', 'relation': 'led to ', 'condition': 'in prostate cancer'}, {'e1': 'TSPAN1 ', 'e2': 'biochemical recurrence ', 'relation': 'was an independent prognosis factor of ', 'condition': 'after radical prostatectomy'}]"
475,P59P1,"Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton’s tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrutinib may be used as an adjuvant treatment for malignant GBM.","[{'e1': ' Btk ', 'e2': 'normal brain cells ', 'relation': 'is significantly higher as compared to ', 'condition': 'in clinical glioma samples'}, {'e1': 'Down-regulation of Btk in GBM cell lines ', 'e2': 'significantly reduced abilities', 'relation': 'showed a ', 'condition': ' in colony formation, migration and GBM sphere-forming potential.'}, {'e1': 'Btk-silenced cells ', 'e2': 'concomitant reduction ', 'relation': 'showed a ', 'condition': 'in the expression of CD133 and Akt/mTOR signaling'}, {'e1': ' our glioma tissue microarray analysis ', 'e2': 'higher Btk staining ', 'relation': 'indicated a ', 'condition': 'in the malignant tumors than less malignant and normal brain tissues. '}]"
476,P59P2,"Malignant brain tumors are challenging to manage clinically due to the nature of highly resistant to chemotherapy and radiotherapy. Recurrence following standard therapeutic regimens, mainly including surgery, radiation therapy, and adjuvant chemotherapy is virtually inevitable. The standard chemotherapeutic agent such as temozolomide (TMZ) promotes DNA damage and disrupts the brain tumor cell mitotic machinery. However, it has only limited effect in prolonging patient survival. Accumulating evidence has suggested that malignant glioma stem cells (GSCs), intrinsic and/or therapy-induced, drive tumor formation and treatment resistance. Thus, identifying agents which can target and eliminate GSCs may improve current therapeutic efficacy in GBM patients.","[{'e1': 'identifying agents which can target and eliminate GSCs ', 'e2': 'current therapeutic efficacy ', 'relation': 'may improve ', 'condition': 'in GBM patients.'}]"
477,P59P3,"The Bruton’s tyrosine kinase (Btk) family kinases consists of non-receptor tyrosine kinases, including Btk/Atk, Bmx/Etk, Itk/Emt/Tsk, and Tec. Accumulating evidence has suggested that Btk family kinases, like Src-family kinases, may play central and diverse modulatory roles in many important cellular processes. Btk regulates key signaling pathways such as PI3K, PLCγ and PKC which suggest their involvements in cellular growth, differentiation and apoptosis. Recently, a new role of this family of kinases is emerging in regulating cytoskeletal reorganization and cell motility. Previously, Btk dysregulation has been mainly attributed to the development of B-cell malignancy. However, recent studies have shown its involvement in solid tumors such as breast, ovary, prostate and lung. Together, these findings provide novel link between Btk and cellular processes such as cellular growth, differentiation, motility and inflammation, all of which if dysregulated, contribute to the progression of cancer.","[{'e1': ' Btk family kinases ', 'e2': 'central and diverse modulatory roles', 'relation': 'may play ', 'condition': ' in many important cellular processes'}, {'e1': 'cellular processes such as cellular growth, differentiation, motility and inflammation', 'e2': 'progression of cancer', 'relation': 'contribute to', 'condition': 'if dysregulated'}]"
478,P59P4,"Interestingly, Btk is recently linked to the activation of NLRP3 inflammasome in ischaemic stroke and as a potential therapeutic target. This finding suggests that Btk is important in neurological development and diseases. However, the role of Btk in the GSC generation has not been explored. This prompts us to investigate Btk’s role in GSC generation and associated malignant phenotypes and mitigating strategies based on Btk inhibition. Here, we first utilized bioinformatics tool and observed a significantly elevated Btk expression in glioma patients as compared to normal brain tissue. Increased Btk expression in GBM spheres was associated with increased stemness, metastatic potential and temozolomide resistance. Btk-silenced GBM cells exhibited a significantly lower ability to form colonies, GBM spheres and metastasize. Notably, ibrutinib (a Btk inhibitor) treatment also led to a similar suppressive effect in GBM malignant phenotypes as observed under gene-silencing conditions. Furthermore, GBM xenograft models demonstrated that down-regulation of Btk via gene-silencing or ibrutinib treatment resulted in a significant reduction in GBM tumorigenesis. Finally, brain tumor tissue microarray data indicated that Btk expression was associated with the disease stage. Collectively, we have provided evidence for targeting Btk using ibrutinib as an alternative and/or adjuvant intervention to the existing therapeutic regimen.","[{'e1': 'Btk ', 'e2': 'activation of NLRP3 inflammasome ', 'relation': 'is recently linked to the ', 'condition': 'in ischaemic stroke'}, {'e1': 'Btk ', 'e2': 'activation of NLRP3 inflammasome ', 'relation': 'is recently linked to the ', 'condition': 'as a potential therapeutic target'}, {'e1': 'a significantly elevated Btk expression', 'e2': 'normal brain tissue', 'relation': ' as compared to ', 'condition': 'in glioma patients'}, {'e1': 'Increased Btk expression', 'e2': 'increased stemness', 'relation': ' was associated with ', 'condition': 'in GBM spheres '}, {'e1': 'Increased Btk expression', 'e2': 'metastatic potential ', 'relation': ' was associated with ', 'condition': 'in GBM spheres '}, {'e1': 'Increased Btk expression', 'e2': 'temozolomide resistance', 'relation': ' was associated with ', 'condition': 'in GBM spheres '}, {'e1': 'ibrutinib (a Btk inhibitor) treatment ', 'e2': 'a similar suppressive effect ', 'relation': 'also led to ', 'condition': 'in GBM malignant phenotypes'}]"
479,P59P5,"Collectively, we have provided a novel association between Btk and GBM malignancy first by bioinformatics approach followed by in vitro and in vivo validation. Notably, clinical tissue arrays revealed that Btk expression was associated with the later stage of the disease. The role of Btk in GSC generation and ability to resist temozolomide treatment via the increased expression of several key stemness/oncogenic molecules including CD133, Nestin, and phosphorylated Akt was also demonstrated. Perceptively, we provide preclinical evidence to support the usage of ibrutinib with temozolomide for the treatment of GBM in mouse xenograft models. This combination may provide improved therapeutic efficacy for GBM patients in clinical settings.","[{'e1': 'the usage of ibrutinib with temozolomide ', 'e2': 'GBM ', 'relation': 'for the treatment of ', 'condition': 'in mouse xenograft models'}, {'e1': 'This combination ', 'e2': 'GBM patients ', 'relation': 'may provide improved therapeutic efficacy for ', 'condition': 'in clinical settings.'}]"
480,P60P1,"Rapid advances in the discovery of long noncoding RNAs (lncRNAs) have identified lineage- and cancer-specific biomarkers that may be relevant in the clinical management of prostate cancer (PCa). Here we assembled and analyzed a large RNA-seq dataset, from 585 patient samples, including benign prostate tissue and both localized and metastatic PCa to discover and validate differentially expressed genes associated with disease aggressiveness. We performed Sample Set Enrichment Analysis (SSEA) and identified genes associated with low versus high Gleason score in the RNA-seq database. Comparing Gleason 6 versus 9+ PCa samples, we identified 99 differentially expressed genes with variable association to Gleason grade as well as robust expression in prostate cancer. The top-ranked novel lncRNA PCAT14, exhibits both cancer and lineage specificity. On multivariate analysis, low PCAT14 expression independently predicts for BPFS, PSS, and MFS, with trends for OS as well. An RNA in-situ hybridization (ISH) assay for PCAT14 distinguished benign vs malignant cases, as well as high vs low Gleason disease. PCAT14 is transcriptionally regulated by AR, and endogenous PCAT14 overexpression suppresses cell invasion. Thus, using RNA-sequencing data we identify PCAT14, a novel prostate cancer and lineage-specific lncRNA. PCAT14 is highly expressed in low grade disease and loss of PCAT14 predicts for disease aggressiveness and recurrence.","[{'e1': 'genes ', 'e2': 'low versus high Gleason score ', 'relation': 'associated with ', 'condition': 'in the RNA-seq database'}, {'e1': '99 differentially expressed genes ', 'e2': 'Gleason grade as well as robust expression ', 'relation': 'with variable association to ', 'condition': 'in prostate cancer'}]"
481,P60P2,"Early detection of prostate cancer, largely facilitated by the advent of PSA screening, has also been attributed to over-diagnosis and overtreatment of this disease. While coupling PSA screening with other biomarkers such as the long non-coding RNA transcript PCA3 or gene fusions events have increased specificity of cancer diagnosis, these biomarkers have limited utility in stratifying patients in terms of prognosis. While stratifying patients into risk groups based on clinicopathologic features is currently used to guide treatment decisions, it is clear that current stratification approaches need to be further refined to allow better personalization of therapy. Thus, identifying molecular biomarkers to distinguish indolent versus aggressive disease would address an unmet need in the clinical management of prostate cancer.","[{'e1': 'identifying molecular biomarkers ', 'e2': ' indolent versus aggressive disease would address an unmet need', 'relation': 'to distinguish', 'condition': ' in the clinical management of prostate cancer.'}]"
482,P60P3,"Advances in next-generation sequencing technologies have enabled thorough characterization of cancer transcriptomes, especially in unraveling the realm of non-coding RNAs. In particular, lncRNAs, a class of ncRNAs, have gained increasing attention as biomarkers due to their tissue- and cancer-specific expression profile. In this study, we assembled and analyzed a large RNA-seq compendium compiled from recent publications from consortiums such as The Cancer Genome Atlas, the Prostate Cancer Foundation/Stand Up to Cancer international team, and others to identify differentially expressed genes, both protein coding and non-coding genes, that are associated with indolent versus aggressive disease. Our results identify PCAT14, a prostate cancer- and lineage-specific lncRNA, as a top differentially expressed gene in this context. We characterize PCAT14 preclinically and demonstrate that it correlates inversely in expression with disease aggressiveness and adds to conventional clinicopathologic risk factors in predicting prognosis in prostate cancer patients. Finally, we develop a novel in-situ hybridization-based approach for detecting PCAT14 in clinical samples.","[{'e1': 'Advances in next-generation sequencing technologies ', 'e2': 'thorough characterization of cancer transcriptomes, ', 'relation': 'have enabled ', 'condition': 'especially in unraveling the realm of non-coding RNAs'}, {'e1': 'PCAT14 ', 'e2': 'disease aggressiveness ', 'relation': 'correlates inversely in expression with ', 'condition': 'in predicting prognosis in prostate cancer patients'}]"
483,P60P4,"By performing differential expression analysis between prostate cancer with low vs high Gleason scores, we identified lncRNA PCAT14 as a prostate cancer- and lineage-specific biomarker of indolent disease. We show that PCAT14 is an AR-regulated transcript and its overexpression suppresses invasion of prostate cancer cells. Moreover, in multiple independent datasets, PCAT14 expression associates with favorable outcomes in prostate cancer and adds prognostic value to standard clinicopathologic variables.","[{'e1': ' PCAT14 expression ', 'e2': 'favorable outcomes ', 'relation': 'associates with ', 'condition': 'in prostate cancer '}]"
484,P61P1,"Genomic loss of chromosome 8p21 region, containing prostate-specific NKX3.1 gene, is a frequent alteration of the prostate cancer oncogenome. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is also associated with a cluster of microRNA genes, miR-3622a/b, that are lost in prostate cancer and play an important mechanistic role in progression and metastasis. In this study, we demonstrate the role of miR-3622b in prostate cancer. Expression analyses in a cohort of prostate cancer clinical specimens and cell lines show that miR-3622b expression is frequently lost in prostate cancer. Low miR-3622b expression was found to be associated with tumor progression and poor biochemical recurrence-free survival. Further, our analyses suggest that miR-3622b expression is a promising prostate cancer diagnostic biomarker that exhibits 100% specificity and 66% sensitivity. Restoration of miR-3622b expression in prostate cancer cell lines led to reduced cellular viability, proliferation, invasiveness, migration and increased apoptosis. miR-3622b overexpression in vivo induced regression of established prostate tumor xenografts pointing to its therapeutic potential. Further, we found that miR-3622b directly represses Epidermal Growth Factor Receptor. In conclusion, our study suggests that miR-3622b plays a tumor suppressive role and is frequently downregulated in prostate cancer, leading to EGFR upregulation. Importantly, miR-3622b has associated diagnostic, prognostic and therapeutic potential. Considering the association of chromosome 8p21 loss with poor prognosis, our findings are highly significant and support a novel concept that associates a long standing observation of frequent loss of a chromosomal region with a novel miRNA in prostate cancer.","[{'e1': 'Restoration of miR-3622b expression ', 'e2': 'reduced cellular viability', 'relation': 'led to ', 'condition': 'in prostate cancer cell lines'}, {'e1': 'Restoration of miR-3622b expression ', 'e2': 'proliferation', 'relation': 'led to ', 'condition': 'in prostate cancer cell lines'}, {'e1': 'Restoration of miR-3622b expression ', 'e2': 'invasiveness', 'relation': 'led to ', 'condition': 'in prostate cancer cell lines'}, {'e1': 'Restoration of miR-3622b expression ', 'e2': 'migration ', 'relation': 'led to ', 'condition': 'in prostate cancer cell lines'}, {'e1': 'Restoration of miR-3622b expression ', 'e2': 'increased apoptosis', 'relation': 'led to ', 'condition': 'in prostate cancer cell lines'}]"
485,P61P2,"Prostate cancer is the most common male malignancy worldwide and a leading cause of cancer related mortality amongst men with an estimated 26,120 deaths predicted for 2016 within the US. Prostate tumors are often indolent and can be effectively managed by active surveillance and watchful waiting. However, a significant proportion of prostate tumors are likely to progress, often metastasizing to bone and other organs causing significant morbidity and mortality. Though novel therapies with marginal survival benefits have been developed for advanced disease, its clinical management remains challenging. Also, prostate cancer is associated with high rates of recurrence, with approximately 40% of men with localized prostate cancer suffering from relapse after initial therapy as monitored by rising PSA and tumor progression to a hormone refractory/castration resistant stage that is essentially untreatable. A major challenge is the elucidation of underlying molecular pathways of prostate cancer progression, recurrence and metastasis that holds enormous potential towards the design of effective therapeutic strategies for better clinical management of the disease.","[{'e1': ' approximately 40% of men with localized prostate cancer', 'e2': 'relapse ', 'relation': ' suffering from ', 'condition': 'after initial therapy '}]"
486,P61P3,"The prostate cancer genome is typically characterized by frequent deletion of chromosome 8p region in 40%-70% cases. Taylor et al. performed large scale integrative analyses of transcriptomes and copy-number alterations in prostate adenocarcinomas and reported chromosome 8p loss as the most frequent genomic alteration. In a recent in silico meta analyses of prostate cancer genomic data from 662 patients (546 primary, 116 advanced tumors), chromosome 8p deletion was reported as the most recurrent copy number alteration. Chromosome 8p losses were reported in 55.7% cases of localized and 90.5% cases of advanced prostate cancer. Association of advanced prostate cancer with a significantly higher deletion frequency of this region suggests its role in disease progression. The minimal region of deletion occurs at chromosome 8p21, which contains prostate-specific NKX3.1 tumor suppressor gene. Also, studies have shown high rate of loss of heterozygosity at chromosome 8p21 subregion that has been associated with prostate-specific homeobox gene NKX3.1. Recent genomic studies suggest the possibility of alternate tumor suppressor genes within this region, apart from NKX3.1. However, the genes within this region are yet to be fully characterized. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is associated with a cluster of microRNA genes, miR-3622a/b, that are lost in prostate cancer and play an important mechanistic role in prostate cancer progression and metastasis. MicroRNAs are endogenous small RNAs that suppress gene expression post transcriptionally via sequence-specific interactions with the 3′- untranslated regions of cognate mRNA targets, and are often located in fragile chromosomal regions involved in cancers. We previously demonstrated that miR-3622a located on frequently deleted chromosome 8p21 region plays a crucial role in prostate cancer epithelial-to-mesenchymal transition, progression and metastasis by direct targeting of ZEB1 and SNAI2. Here we examined the role of another member of the cluster, miR-3622b, in prostate cancer and show its crucial tumor suppressive role. miR-3622b is a recently discovered miRNA gene that has not been studied. Expression analyses in a cohort of prostate cancer clinical specimens showed that miR-3622b expression is frequently lost in prostate cancer and correlated with poor recurrence-free survival outcome and tumor progression. Our in vitro and in vivo studies support a tumor suppressive role of miR-3622b in prostate cancer, mediating its effects largely by directly repressing Epidermal Growth Factor Receptor. Thus, our data support a novel concept, linking the long standing observation of frequent loss of chromosome 8p21 in prostate cancer, with the loss of a novel miRNA gene within this region.","[{'e1': 'The prostate cancer genome ', 'e2': 'frequent deletion of chromosome 8p region', 'relation': 'is typically characterized by ', 'condition': ' in 40%-70% cases'}, {'e1': 'Taylor et al. ', 'e2': 'large scale integrative analyses of transcriptomes and copy-number alterations ', 'relation': 'performed ', 'condition': 'in prostate adenocarcinomas'}, {'e1': ' this frequently deleted locus ', 'e2': ' a cluster of microRNA genes, miR-3622a/b ', 'relation': 'is associated with', 'condition': 'in prostate cancer progression and metastasis'}]"
487,P61P4,"In conclusion, our study shows that miR-3622b is frequently downregulated in prostate cancer leading to upregulation of EGFR and culminating in effects on cell survival, proliferation, apoptosis and invasion. In view of our present results and our earlier study on miR-3622a, we propose that the miR-3622a/b cluster at frequently deleted chromosome 8p21 locus plays important mechanistic roles in prostate cancer by regulating cardinal genes involved in tumorigenesis. Frequent loss of miR-3622a/b cluster at chromosome 8p21 region causes downregulation of these genes leading to prostate cancer progression. Considering the association of chromosome 8p21 loss with tumor progression and poor prognosis in prostate cancer, our findings are highly significant as they support a novel concept that connects a long standing observation of frequent loss of a chromosomal region with a novel miRNA cluster in prostate cancer. Importantly, these miRNAs also have prognostic, diagnostic and therapeutic potential in the treatment of prostate cancer.","[{'e1': 'the miR-3622a/b cluster at frequently deleted chromosome 8p21 locus ', 'e2': 'important mechanistic roles ', 'relation': 'plays ', 'condition': 'in prostate cancer by regulating cardinal genes involved in tumorigenesis'}, {'e1': ' chromosome 8p21 loss', 'e2': ' tumor progression ', 'relation': 'associated with ', 'condition': 'in prostate cancer'}, {'e1': ' chromosome 8p21 loss', 'e2': 'poor prognosis ', 'relation': 'associated with ', 'condition': 'in prostate cancer'}, {'e1': ' a novel concept ', 'e2': 'a long standing observation of frequent loss of a chromosomal region with a novel miRNA cluster', 'relation': 'that connects ', 'condition': ' in prostate cancer'}, {'e1': 'these miRNAs ', 'e2': 'prognostic, diagnostic and therapeutic potential', 'relation': 'also have ', 'condition': ' in the treatment of prostate cancer.'}]"
488,P62P1,"Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Statistical analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy.","[{'e1': 'PTEN, a critical tumor and metastasis suppressor gene ', 'e2': 'cell survival, proliferation, migration and angiogenesis ', 'relation': 'negatively regulates ', 'condition': 'via the PI3K/Akt pathway'}, {'e1': 'PTEN dysregulation ', 'e2': 'poor prognosis ', 'relation': 'correlates with ', 'condition': 'in PCa'}, {'e1': 'Knockdown of miR-4534 ', 'e2': 'cell proliferation', 'relation': 'impaired ', 'condition': 'in PCa'}, {'e1': 'Knockdown of miR-4534 ', 'e2': 'migration/invasion', 'relation': 'impaired ', 'condition': 'in PCa'}, {'e1': 'Knockdown of miR-4534 ', 'e2': 'G0/G1 cell cycle arrest ', 'relation': ' induced ', 'condition': 'in PCa'}, {'e1': 'Knockdown of miR-4534 ', 'e2': 'apoptosis ', 'relation': ' induced ', 'condition': 'in PCa'}, {'e1': ' depletion of miR-4534', 'e2': 'a tumor suppressor phenotype ', 'relation': ' induces ', 'condition': 'in PCa partly through induction of PTEN'}, {'e1': 'These results ', 'e2': 'new PTEN regulators such as microRNAs', 'relation': 'have important implications for identifying and defining the role of ', 'condition': ' in prostate tumorigenesis'}]"
489,P62P2,"Prostate cancer is the second most prevalent cause of cancer deaths among males in the United States and the fourth most common tumor type worldwide. According to recent data, it is estimated that 220, 800 newly diagnosed prostate cancer cases and 27, 540 deaths will occur in 2015. The five year relative survival rate of early stage prostate cancer is > 99% while that of advanced metastatic disease is only 28%. The clinical behavior of localized prostate cancer is highly variable, while some men have aggressive cancer leading to metastasis and death from the disease, many others have indolent cancers that are cured with initial therapy or may be safely observed. Multiple risk stratification systems have been developed, combining the best currently available clinical and pathological parameters (such as Gleason score, PSA levels and clinical and pathological staging); however, several areas of urgent unmet need remain, e.g., a validated biomarker to complement PSA for screening, prognostic biomarkers with clinical utility, further risk stratification using molecular differentiation could potentially help distinguish indolent from aggressive prostate cancer. Prostate carcinogenesis features alterations in several signaling pathways, the most prominent of which is the highly oncogenic prosurvival PI3K/AKT signaling pathway. In human prostate cancer, the PI3K/Akt pathway is frequently activated due to inactivation of PTEN.","[{'e1': 'the PI3K/Akt pathway ', 'e2': 'inactivation of PTEN.', 'relation': 'is frequently activated due to ', 'condition': 'In human prostate cancer'}]"
490,P62P3,"PTEN (phosphatase and tensin homolog deleted on chromosome 10; also known as MMAC1 and TEP1) is one of the most frequently altered tumor suppressor genes in cancer, and in particular, prostate cancer. It catalyzes the conversion of the membrane lipid second messenger PIP3 to PIP2 and is therefore a key mediator of the PI3K/Akt pathway. PTEN levels have been identified as being critical in determining the mechanism by which prostate tumors evolve in vivo. PTEN heterozygosity has been shown to promote tumor initiation and proliferation. In addition, primary tumors often show loss or alteration of at least one PTEN allele in 70%–80% of primary prostate cancers, while homozygous inactivation of PTEN is generally associated with advanced cancer and metastasis. Functionally, PTEN is a nonredundant, plasma-membrane lipid phosphatase and its inactivation upregulates PI3K/AKT signaling enhancing protein synthesis, cell migration and tumor-induced angiogenesis. PTEN has been reported to be repressed by oncogenic microRNAs (miRNA), e.g., miRNA-21, -214, -301 in many cancers, suggesting that oncogenic activity of these miRNAs is in part through downregulation of PTEN. Although not much work has been done on oncogenic miRNAs as compared to tumor suppressor miRNAs, it is very interesting that miRNAs may influence carcinogenesis through PTEN regulation.","[{'e1': 'miRNAs ', 'e2': 'carcinogenesis', 'relation': 'may influence ', 'condition': 'through PTEN regulation.'}]"
491,P62P4,"MicroRNAs (miRNAs) are a naturally-occurring class of short, non-coding RNA molecules between 19 and 21 nucleotides long. In humans approximately 2,8645 unique mature miRNAs have been identified. While the exact function of miRNAs remain to be fully elucidated, they are known to regulate gene expression via binding target messenger RNA (mRNA), inhibiting translation or triggering mRNA degradation. Importantly, it has been demonstrated that in addition to their inhibitory role, miRNAs can also induce or activate transcript levels. Through these mechanisms miRNAs perform a regulatory role in various cellular processes, including cell development, differentiation, proliferation and apoptosis. Dysregulated miRNA expression patterns have been noted in many organisms, encompassing a wide spectrum of pathological processes, from immunological defects in fish, altered developmental phase transition and flowering time in plants, and neurodegeneration, cardiovascular disease and cancer in humans. Discovery of dysregulated miRNA expression has led to the hypothesis that miRNAs could potentially be used as disease diagnostic or prognostic markers. Furthermore, miRNA are attractive therapeutic targets for the treatment of various conditions, including cancer. At present, multiple clinical trials are currently registered with ClinicalTrials.gov, investigating the ability of miRNA to function as disease biomarkers and response to current therapies. The novel role of miRNA and their importance in many different processes has led to an explosion of scientific enquiry into miRNA function. Thus the aim of this study is to understand the role of microRNA-4534 (miR-4534) dysregulation in promoting prostate oncogenesis. miR-4534 was selected based on our previous study that we performed to preliminary screen and identify differentially expressed miRNAs in prostate cancer cell lines compared to a non-malignant cell line. A set of miRNAs, miR-205, -203, 23b and -34b were found to be significantly downregulated whereas miR-4534 was significantly upregulated in prostate cancer cells compared to a non-malignant cell line.","[{'e1': ' miRNAs ', 'e2': 'gene expression ', 'relation': 'are known to regulate ', 'condition': 'via binding target messenger RNA (mRNA)'}]"
492,P62P5,"In this study we report that: (i) miR-4534 is overexpressed in prostate cancer tissues and cell lines compared to matched normal samples and cell lines; (ii) miR-4534 has potential to distinguish malignant from normal tissues; (iii) miR-4534 functions as an oncomiR as its attenuation results in cell cycle arrest, apoptosis, impaired migration/invasion and colony forming capability of prostate cancer cells; (iv) miR-4534 directly targets PTEN and its downstream effectors to exert its functional effects; (v) intra-tumoral delivery of anti-miR-4534 (anti4534) inhibits in-vivo tumor growth in nude mice xenografts.","[{'e1': 'intra-tumoral delivery of anti-miR-4534 (anti4534) ', 'e2': 'in-vivo tumor growth ', 'relation': 'inhibits ', 'condition': 'in nude mice xenografts.'}]"
493,P62P6,"In summary, our study has identified novel oncogenic miR-4534 harbored at locus Chr22q13.1 that is implicated in aggressive prostate cancer. miR-4534 expression has clinical significance to be a diagnostic/prognostic biomarker as it can diagnose prostate cancer from normal tissues and is positively correlated with poor overall and recurrence free survival. We also found that miR-4534 is overexpressed in prostate cancer and directly targets PTEN leading to its downregulation. Furthermore, induction of PTEN could be achieved by miR-4534 depletion, which caused significant inhibition of tumorigenesis in prostate cancer cells. We conclude that therapeutic modulation of miR-4534 in prostate tumors provides an alternative option for the management of prostate cancer.","[{'e1': 'miR-4534 depletion', 'e2': 'significant inhibition of tumorigenesis ', 'relation': ' caused ', 'condition': 'in prostate cancer cells'}, {'e1': 'therapeutic modulation of miR-4534 ', 'e2': 'an alternative option for the management of prostate cancer.', 'relation': 'provides ', 'condition': ' in prostate tumors'}]"
494,P63P8,"In conclusion, we have identified PTGS2 rs4648302 as a prognostic predictor for prostate cancer. This variant might alter microRNA binding, and thus influence PTGS2 expression and prostate cancer progression. Clinical studies have suggested that selective PTGS2 inhibitors could reduce cancer risk. If validated, such knowledge could ultimately lead to targeted therapies for a subset of high-risk patients harboring this inherited PTGS2 variant.","[{'e1': ' such knowledge ', 'e2': 'targeted therapies', 'relation': 'could ultimately lead to ', 'condition': 'If validated'}]"
495,P65P1,"Identifying the subset of patients with clinically localized prostate cancer (PCa) at the highest risk of recurrence remains challenging, and better prognostic markers are needed. Gleason score is the best predictor of PCa aggressiveness and prognosis. In the present study, we generated an epigenetic signature based on high versus low Gleason score tumors and evaluated its ability to predict recurrence after radical prostatectomy.","[{'e1': 'an epigenetic signature based on high versus low Gleason score tumors ', 'e2': ' recurrence ', 'relation': 'and evaluated its ability to predict', 'condition': 'after radical prostatectomy.'}]"
496,P65P2,Genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA; no. of patients = 333) and the elastic net method were used to generate an epigenetic signature by contrasting patients with high (8–10) versus low (≤6) Gleason score tumors. The signature was then tested in a cohort of 523 patients with clinically localized disease who had radical prostatectomy. Samples taken from the primary tumor were used for DNA methylation and mRNA expression profiling. Patients were followed for PCa recurrence on average for 8 years after diagnosis.,"[{'e1': 'Patients ', 'e2': 'PCa recurrence on average for 8 years ', 'relation': 'were followed for ', 'condition': 'after diagnosis.'}]"
497,P65P3,"The epigenetic signature includes 52 differentially methylated CpG sites. In the testing cohort, the signature was associated with poorer recurrence-free survival (hazard ratio per 25% increase = 1.78; 95% confidence interval 1.48, 2.16). The signature significantly improved the area under the curve (AUC) for PCa recurrence compared to clinical-pathological parameters alone, particularly among patients diagnosed with Gleason score 7 tumors (0.64 vs. 0.76, P = 1.34E‚àí4). Results were comparable for patients with Gleason 3 + 4 and those with 4 + 3 tumors. Gene Set Enrichment Analysis showed that higher levels of the signature were associated with increased expression of genes related to cell cycle proliferation and decreased expression of androgen-responsive genes.","[{'e1': 'The signature ', 'e2': 'the area under the curve (AUC) for PCa recurrence', 'relation': 'significantly improved ', 'condition': ' particularly among patients diagnosed with Gleason score 7 tumors'}]"
498,P65P4,This report shows evidence that DNA methylation patterns measured in prostate tumor cells are predictive of PCa aggressiveness. The epigenetic signature may have clinical utility to improve prognostication particularly in patients with intermediate Gleason score 7 tumors.,"[{'e1': 'The epigenetic signature ', 'e2': 'prognostication ', 'relation': 'may have clinical utility to improve ', 'condition': 'particularly in patients with intermediate Gleason score 7 tumors.'}]"
499,P65P6,"DNA methylation is an epigenetic alteration that occurs at CG dinucleotides (CpG sites). The human DNA methylome is generated in a programmed manner during normal development and methylation patterns change as a result of aging. Patterns of DNA methylation record a remarkable breadth of information about cells, including their chronological age, developmental history, and differentiation potential. In PCa, there is substantial heterogeneity in tumor DNA methylation profiles, and these epigenetic changes may also predict PCa aggressiveness. Some previous studies showed that differentially methylated CpG sites in specific genes are associated with more aggressive and advanced PCa, but most of these investigations focused on selected candidate genes and findings require validation.","[{'e1': 'differentially methylated CpG sites ', 'e2': 'more aggressive and advanced PCa', 'relation': 'are associated with ', 'condition': ' in specific genes'}]"
500,P65P7,"In this study, we generated an epigenetic (DNA methylation) signature for use as a prognostic classifier in PCa. Because Gleason score is the best predictor of PCa prognosis, we generated the signature by contrasting patients with high (8–10) versus low (≤6) Gleason score tumors. The signature was then tested for its ability to predict recurrence in a validation cohort of patients with clinically localized PCa who had radical prostatectomy.","[{'e1': 'an epigenetic (DNA methylation) signature ', 'e2': 'a prognostic classifier ', 'relation': 'for use as ', 'condition': 'in PCa'}]"
501,P65P8,"Better tools to identify at the time of diagnosis the subset of PCa patients at the highest risk of recurrence are urgently needed. Our study provides new evidence that DNA methylation profiling has the clinical potential to improve risk prediction for PCa outcomes in patients with clinically localized disease, particularly in patients with Gleason score 7 tumors, which have a variable clinical course and represent a substantial proportion of prostate cancer patients diagnosed worldwide each year.","[{'e1': ' DNA methylation profiling ', 'e2': 'risk prediction for PCa outcomes ', 'relation': 'has the clinical potential to improve ', 'condition': 'in patients with clinically localized disease'}, {'e1': ' DNA methylation profiling ', 'e2': 'risk prediction for PCa outcomes ', 'relation': 'has the clinical potential to improve ', 'condition': 'particularly in patients with Gleason score 7 tumors'}]"
502,P66P1,"The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle (“Cell Cycle Common”), versus those that were specifically enriched in a subset of cell cycle phases (“Phase Restricted”). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide-desaturase 1 (DEGS1) was identified as an AR regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention, and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.","[{'e1': 'Analyzing AR activity as a function of cell cycle ', 'e2': 'AR-regulated gene networks ', 'relation': 'revealed an unexpected and highly expanded repertoire of ', 'condition': 'in actively cycling cells'}, {'e1': 'dihydroceramide-desaturase 1 (DEGS1) ', 'e2': ' AR regulated gene', 'relation': 'was identified as an', 'condition': ' in mitotically active cells that promoted pro-metastatic phenotypes'}, {'e1': 'previously unrecognized AR functions ', 'e2': 'clinical PCa progression', 'relation': 'associated with ', 'condition': 'in major pathways'}, {'e1': 'dihydroceramide-desaturase 1 (DEGS1) ', 'e2': 'with development of metastases', 'relation': ' proved to be highly associated ', 'condition': 'in advanced PCa'}, {'e1': 'dihydroceramide-desaturase 1 (DEGS1) ', 'e2': 'recurrence ', 'relation': ' proved to be highly associated ', 'condition': 'after therapeutic intervention'}, {'e1': 'these findings ', 'e2': 'AR function ', 'relation': 'delineate ', 'condition': 'in mitotically active tumor cells'}]"
503,P66P2,"Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy in the USA, and the second most lethal form of cancer. While localized disease is readily treatable through surgery and/or radiation, there is no curative intervention for advanced PCa. Advanced PCa typically remains reliant on androgen receptor (AR) signaling throughout disease progression. As a hormone nuclear receptor, AR requires androgen (testosterone or dihydrotestestone, DHT) binding for activation. Once active, AR binds DNA and initiates transcriptional programs required for proliferation and survival, however the mechanisms governing these events have remained largely elusive. By contrast, the mechanism by which AR regulates proteases important for prostate function (e.g. Prostate Specific Antigen, PSA, encoded by KLK3), are well known, and PSA is used clinically to monitor tumor development and progression. Given the exquisite dependence of PCa on AR function, therapy for disseminated disease suppresses AR signaling, achieved by ablation of circulating ligand (androgen deprivation therapy, ADT), often used in combination with direct AR antagonists. While initially efficacious, these regimens ultimately fail and castration resistant prostate cancer (CRPC) develops due to reactivation of the AR signaling axis. At present, there remain no durable means to manage recurrent AR activity and treat CRPC; as such developing understanding of AR function and mechanisms to target downstream processes represents a primary focus in the field.","[{'e1': 'Advanced PCa ', 'e2': 'on androgen receptor (AR) signaling ', 'relation': 'typically remains reliant ', 'condition': 'throughout disease progression'}]"
504,P66P4,"Studies herein reveal that AR induces differential transcriptional networks in mitotically active cells, unmasking critical new insight into AR function. Molecular dissection demonstrated that networks specific to actively cycling cells can be subdivided into those that are common to all active phases of the cell cycle, versus those that are specifically enriched in distinct cell cycle phases. Networks identified were strongly associated with novel AR cistromes through genome-wide binding analyses, demonstrating the unexpected finding that AR function is significantly expanded in cells committed to the mitotic cell cycle, and that AR function is sensitive to cell cycle position. Functional analyses unveiled novel mechanisms through which AR likely promotes pro-tumorigenic phenotypes including cell migration and tumor metastases. Of particular significance was the discovery of DEGS1, a desaturase involved primarily in the formation of ceramide, as a key target through which AR promotes pro-metastatic phenotypes. Analyses in human tumor samples further identified DEGS1 as strongly associated with disease progression and poor outcome, outperforming current biomarkers of aggressive disease. Taken together, the studies herein demonstrate that AR signaling is widely expanded in mitotically active cells, and promotes pro-tumorigenic networks underpinning cancer progression.","[{'e1': 'AR ', 'e2': 'differential transcriptional networks ', 'relation': 'induces ', 'condition': 'in mitotically active cells'}, {'e1': 'Networks identified ', 'e2': 'novel AR cistromes ', 'relation': 'were strongly associated with ', 'condition': 'through genome-wide binding analyses'}, {'e1': ' DEGS1 ', 'e2': 'disease progression and poor outcome', 'relation': 'was strongly associated with ', 'condition': 'in human tumor samples'}]"
505,P66P5,"Taken together, molecular assessment of AR activity not only reveals differential function across the cell cycle and illuminates new understanding of the mechanisms by which AR promotes disease progression, but underscore the importance of discerning cancer-promoting transcription factor function in mitotically active cells. The present findings yield critical new insight into AR function and nominate downstream effectors of AR activity as potentially impactful therapeutic targets and biomarkers of lethal disease phenotypes.","[{'e1': ' molecular assessment of AR activity', 'e2': 'the importance of discerning cancer-promoting transcription factor function', 'relation': 'underscore ', 'condition': ' in mitotically active cells'}]"
506,P67P1,"The prostanoid thromboxane (TX)A2 plays a central role in haemostasis and is increasingly implicated in cancer progression. TXA2 signals through two T Prostanoid receptor (TP) isoforms termed TPα and TPβ, with both encoded by the TBXA2R gene. Despite exhibiting several functional and regulatory differences, the role of the individual TP isoforms in neoplastic diseases is largely unknown.","[{'e1': 'The prostanoid thromboxane (TX)A2 ', 'e2': 'a central role ', 'relation': 'plays ', 'condition': 'in haemostasis '}]"
507,P67P2,"This study evaluated expression of the TPα and TPβ isoforms in tumour microarrays of the benign prostate and different pathological (Gleason) grades of prostate cancer (PCa). Expression of TPβ was significantly increased in PCa relative to benign tissue and strongly correlated with increasing Gleason grade. Furthermore, higher TPβ expression was associated with increased risk of biochemical recurrence (BCR) and significantly shorter disease-free survival time in patients post-surgery. While TPα was more variably expressed than TPβ in PCa, increased/high TPα expression within the tumour also trended toward increased BCR and shorter disease-free survival time. Comparative genomic CpG DNA methylation analysis revealed substantial differences in the extent of methylation of the promoter regions of the TBXA2R that specifically regulate expression of TPα and TPβ, respectively, both in benign prostate and in clinically-derived tissue representative of precursor lesions and progressive stages of PCa. Collectively, TPα and TPβ expression is differentially regulated both in the benign and tumourigenic prostate, and coincides with clinical pathology and altered CpG methylation of the TBXA2R gene. Analysis of TPβ, or a combination of TPα/TPβ, expression levels may have significant clinical potential as a diagnostic biomarker and predictor of PCa disease recurrence.","[{'e1': 'This study ', 'e2': 'the TPα and TPβ isoforms ', 'relation': 'evaluated expression of ', 'condition': 'in tumour microarrays of the benign prostate '}, {'e1': 'This study ', 'e2': 'the TPα and TPβ isoforms ', 'relation': 'evaluated expression of ', 'condition': 'in different pathological (Gleason) grades of prostate cancer (PCa)'}, {'e1': 'higher TPβ expression ', 'e2': 'increased risk of biochemical recurrence (BCR) ', 'relation': 'was associated with ', 'condition': 'in patients post-surgery'}, {'e1': 'higher TPβ expression ', 'e2': 'significantly shorter disease-free survival time ', 'relation': 'was associated with ', 'condition': 'in patients post-surgery'}]"
508,P67P4,"By now numerous epidemiological studies have shown that regular intake of the non-steroidal anti-inflammatory drug (NSAID) aspirin, an inhibitor of the cyclooxygenases (COXs), substantially reduces risks in both the incidence and progression of several prevalent cancers, including PCa. While those studies do not specify which COX-1/2 metabolite(s) are actually lowered by aspirin accounting for its prophylactic benefits, recent studies suggest that some/much of its anti-cancer effects may be due to its ability to inhibit thromboxane (TX)A2 generation, a prostanoid more typically implicated in thrombosis and cardiovascular disease. Increased levels of TXA2 and expression of its synthase and its T prostanoid receptor, the TP, have been found in a number of prevalent cancers and, mechanistically, the role of TXA2 in cancer may be explained by the ability of the TXA2-TP axis to regulate key mitogenic/extracellular signal regulated kinase (ERK)- and RhoA-mediated signalling cascades that contribute to tumour development and metastasis. For example, increased levels of TXA2, TXA2 synthase and the TP strongly correlate with bladder, prostate, colorectal and non-small cell lung cancer. Furthermore, it has long been known that platelets, the main source of TXA2 and key target of aspirin, play a central role in tumour progression promoting cancer cell metastasis, immune evasion and extravasation.","[{'e1': 'the non-steroidal anti-inflammatory drug (NSAID) aspirin ', 'e2': ' risks ', 'relation': 'substantially reduces', 'condition': 'in both the incidence and progression of several prevalent cancers, including PCa'}]"
509,P67P7,"In conclusion, data presented herein propose a novel diagnostic and prognostic potential for TPα and TPβ in the histopathological assessment of PCa. While TPα and TPβ are differentially expressed and independently regulated, increased levels of TPβ, TPα or both correlated with increased risk of recurrence and reduced disease-free survival time. Moreover, correlation of TPα and TPβ expression with pathological staging showed that high TPα expression was significantly associated with the organ-confined pT2 cases while, in stark contrast, high TPβ expression was significantly associated with the invasive pT3 cases. We also show that altered CpG methylation of the Prm1 and Prm3 regions of TBXA2R gene can specifically modulate TPα and TPβ expression, respectively, during the progression of PCa. Following detailed investigation of the trans-acting transcription factors regulating Prm1/TPα and Prm3/TPβ in PCa settings, interrogation of the CpG methylation status of the TBXA2R might also serve as a key clinical marker with which to stratify higher risk patients and to tailor treatment options.","[{'e1': ' altered CpG methylation of the Prm1 and Prm3 regions of TBXA2R gene ', 'e2': 'TPα and TPβ expression', 'relation': 'can specifically modulate ', 'condition': ' during the progression of PCa'}]"
510,P67P8,"Taken together, these studies provide significant credence to the functional role of the TXA2-TP signalling axis in cancer progression and to the growing body of evidence for the prophylactic benefits of aspirin in reducing cancer risk by lowering TXA2 levels. Whether there is a particular added clinical benefit of aspirin therapy in those patients showing elevated TPβ or TPα needs to be considered. Furthermore, investigation of the therapeutic potential of targeting TPβ and/or TPα through the use of receptor antagonists, such as in adjuvant therapy, for PCa treatment may also be warranted.","[{'e1': 'these studies ', 'e2': 'the functional role of the TXA2-TP signalling axis ', 'relation': 'provide significant credence to ', 'condition': 'in cancer progression'}]"
511,P68P3,"CDO1 was hypermethylated in PCa compared to normal adjacent tissues and benign prostatic hyperplasia and was associated with reduced gene expression. Using two different methodologies for methylation quantification, high CDO1 methylation as continuous variable was associated with BCR in univariate analysis in both cohorts but failed to reach statistical significance in multivariate analysis.","[{'e1': 'CDO1 ', 'e2': 'with reduced gene expression', 'relation': 'was associated ', 'condition': 'in PCa'}, {'e1': 'high CDO1 methylation as continuous variable ', 'e2': ' BCR ', 'relation': 'was associated with', 'condition': 'in univariate analysis in both cohorts'}]"
512,P68P4,CDO1 promoter methylation is involved in gene regulation and is a potential prognostic biomarker for BCR-free survival in PCa patients following radical prostatectomy. Further studies are needed to validate CDO1 methylation assays and to evaluate the clinical utility of CDO1 methylation for the management of PCa.,"[{'e1': 'CDO1 promoter methylation ', 'e2': 'gene regulation ', 'relation': 'is involved in ', 'condition': 'in PCa patients following radical prostatectomy'}, {'e1': 'CDO1 promoter methylation ', 'e2': 'BCR-free survival ', 'relation': 'is a potential prognostic biomarker for ', 'condition': 'in PCa patients following radical prostatectomy'}]"
513,P68P6,"So far, immunohistochemical biomarkers have not been proven successful and may not represent an ideal basis for a robust prognostic test, whereas nucleic acid-based biomarkers appear more promising. Changes in DNA promoter methylation of human genes are of great potential to serve as biomarkers, as they are one of the most common epigenetic alterations in malignant tumors. Furthermore, DNA is highly stable and can be extracted from different materials, for example formalin-fixed paraffin-embedded tissues and body fluids. It has previously been shown that the methylation level of the cysteine dioxygenase 1 (CDO1) promoter region is associated with metastasis in estrogen receptor-positive, lymph node-positive breast cancer patients receiving adjuvant anthracycline treatment. This result was confirmed in a second, independent study. Jeschke and colleagues could demonstrate that CDO1 silencing contributes to reactive oxygen species detoxification capacity and leads to a resistance against reactive oxygen species-generating chemotherapeutics including anthracyclines. Only recently, another study reported that CDO1 promoter hypermethylation has a prognostic value in primary breast cancer patients. Additional studies have shown hypermethylation of the CDO1 promoter region in several solid tumors, such as esophageal, bronchial, urinary bladder, gastric, cholangiocarcinomas, or colorectal carcinomas. Moreover, a correlation between CDO1 promoter hypermethylation and poor survival has been demonstrated in clear cell renal cell carcinoma patients.","[{'e1': 'Changes in DNA promoter methylation of human genes ', 'e2': 'biomarkers', 'relation': 'are of great potential to serve as ', 'condition': ' in malignant tumors. '}, {'e1': 'the methylation level of the cysteine dioxygenase 1 (CDO1) promoter region ', 'e2': 'metastasis ', 'relation': 'is associated with ', 'condition': 'in estrogen receptor-positive'}, {'e1': 'CDO1 promoter hypermethylation ', 'e2': 'poor survival ', 'relation': 'correlates with', 'condition': 'in clear cell renal cell carcinoma patients.'}]"
514,P69P1,"Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.","[{'e1': 'Chronic activation of Notch1 ', 'e2': 'multiple oncogenic pathways altered ', 'relation': 'synergizes with ', 'condition': 'in early disease to promote the development of prostate adenocarcinoma'}, {'e1': 'the Notch1 signaling axis ', 'e2': 'alternative pathways ', 'relation': 'synergizes with ', 'condition': 'in promoting metastatic CRPC'}]"
515,P69P3,"The Notch family of receptors regulates cell-fate determination throughout development in many organ systems, including the prostate. In neonatal and adult mouse prostate tissues, disruption of Notch signaling inhibits prostate epithelial cell differentiation. Notch homolog 1, translocation-associated (Notch1) was also shown to promote mouse luminal prostate cell survival and proliferation through the activation of the prosurvival NF-κB pathway. Elevated expression of the Notch ligand Jagged1 has been associated with metastatic prostate cancer, and down-regulation of Notch1 and Jagged1 in human prostate cancer cell lines decreases in vitro invasion and cell growth. In addition, chemoresistance in human prostate cancer cells has been linked to the activation of Notch2 receptors. Despite these studies, direct evaluation of Notch receptors as drivers of aggressive prostate cancer and the relationship of Notch receptors with other commonly altered pathways in prostate tumorigenesis remain unclear.","[{'e1': 'Notch homolog 1, translocation-associated (Notch1) ', 'e2': 'mouse luminal prostate cell survival and proliferation ', 'relation': 'was also shown to promote ', 'condition': 'through the activation of the prosurvival NF-κB pathway'}, {'e1': 'down-regulation of Notch1 and Jagged1 ', 'e2': 'in vitro invasion and cell growth', 'relation': 'decreases ', 'condition': 'in human prostate cancer cell lines'}]"
516,P69P4,"The canonical Notch pathway is activated through binding of Notch ligands to Notch receptors. Ligand binding induces Notch-receptor cleavage through regulated intramembrane proteolysis, a multistep process carried out by members of the A Disintegrin and Metalloprotease family within the extracellular region and by the γ-secretase complex within the transmembrane domain of Notch cell-surface receptors. Upon cleavage, the Notch intracellular domain is released and translocates to the nucleus, where it is referred to as activated Notch. NICD serves as a transcriptional coactivator that in turn regulates a set of genes involved in proliferation, self-renewal, survival, and differentiation.","[{'e1': 'Ligand binding ', 'e2': 'Notch-receptor cleavage ', 'relation': 'induces ', 'condition': 'through regulated intramembrane proteolysis'}]"
517,P69P5,"Components of the Notch signaling pathway are altered in multiple cancers. Interestingly, Notch signaling previously has been reported to function as both a tumor suppressor and an oncogene. The dependency of Notch1 function in cancer may be tissue specific and context dependent. Loss-of-function mutations in Notch receptors support their tumor-suppressive role in multiple malignancies, including bladder cancer and squamous cell carcinoma. Constitutive activation of the Notch receptors through gene rearrangements or mutations leads to Notch receptors’ oncogenic function in 55–60% of patients with T-cell acute lymphoblastic leukemia. An oncogenic role of Notch1 also has been demonstrated in chronic lymphocytic leukemia and in solid tumors such as lung adenocarcinoma and others. Mutations within Notch1 receptor are rare in metastatic prostate cancer.","[{'e1': 'Constitutive activation of the Notch receptors through gene rearrangements or mutations ', 'e2': 'Notch receptors’ oncogenic function', 'relation': 'leads to ', 'condition': ' in 55–60% of patients with T-cell acute lymphoblastic leukemia'}]"
518,P69P6,"Here we report significantly elevated levels of nuclear NICD1 in hormone-naive high-risk prostate cancer and nearly all metastatic CRPC specimens but not in benign tissues or low- and intermediate-risk localized prostate cancer. Although overexpression of NICD1 alone was not sufficient to drive prostate tumorigenesis, NICD1 in combination with components of pathways commonly altered in early prostate cancer, such as myristoylated AKT, Myc, and Ras/Raf/MAPK, promoted the development of aggressive prostate adenocarcinoma and progression to CRPC. Consistent with their aggressiveness, these tumors displayed an epithelial-to-mesenchymal transition phenotype, high self-renewal, and the potential for metastatic colonization. Tumors driven by NICD1 in combination with myristoylated AKT, Myc, and the Ras/Raf/MAPK pathway are also resistant to androgen deprivation. Our results indicate that Notch1 receptor signaling plays a central role in the development and progression of prostate cancer and may serve as a rational therapeutic target in high-risk prostate cancer and metastatic CRPC.","[{'e1': 'Notch1 receptor signaling', 'e2': 'rational therapeutic target ', 'relation': ' serve as a ', 'condition': 'in high-risk prostate cancer and metastatic CRPC.'}]"
519,P69P7,We provide functional evidence that NICD1 synergizes with multiple pathways in driving poorly differentiated prostate adenocarcinoma and metastatic CRPC in vivo. Our results suggest that activation of Notch1 may serve as a biomarker to predict the potential benefit of Notch1 inhibition and as a therapeutic target for patients suffering from metastatic CRPC.,"[{'e1': 'NICD1 ', 'e2': 'multiple pathways ', 'relation': 'synergizes with ', 'condition': 'in driving poorly differentiated prostate adenocarcinoma and metastatic CRPC in vivo'}]"
520,P70P11,"However, a lower positive sample fraction level can be expected due to our smaller effective sample volume and high stringency in tumor cell calling. In this study, we only include tumor cells defined by their relatively large size, nuclear morphology, and cytokeratin-positive/CD45-negative expression profile, but other less well-characterized tumor cell populations exist.","[{'e1': 'a lower positive sample fraction level ', 'e2': 'our smaller effective sample volume and high stringency ', 'relation': 'can be expected due to ', 'condition': 'in tumor cell calling'}]"
521,P70P12,"Our data support the clinical potential of profiling tumor cells in bone marrow aspirates together with blood in metastatic prostate cancer. Although more invasive than blood draws, bone marrow aspirates are less uncomfortable than bone marrow biopsies, relatively easy and quick to obtain by trained personnel with minimal complications, thus allowing for low-frequency serial collection in a prostate cancer clinic. We found the fraction of positive bone marrow aspirates, 35% overall, 25% in metastatic castration-sensitive disease and 39% in metastatic castration-resistant disease, in metastatic patients to be slightly higher than that of blood specimens, 28% overall, 18% in metastatic castration-sensitive disease and 33% in metastatic castration-resistant disease. More significantly, of 38 cases with paired bone marrow aspirate and blood available in which at least one of the two was positive for tumor cells, in 17, the bone marrow aspirate was the only positive, while only 7 had detectable circulating tumor cells but no metastatic tumor cells in the corresponding bone marrow aspirate. In the remaining 14 patients, both metastatic tumor cells and circulating tumor cells were identified. Likewise, although circulating tumor cells and metastatic tumor cells generally correlated in terms of proportions of androgen receptor-positive and androgen receptor-negative cells and clonal diversity in the paired specimens available, the much higher median number of tumor cells in the positive bone marrow aspirates than in the blood, 536 vs. 10 cells/mL, respectively, allowed for more detailed characterization of the tumor's composition.","[{'e1': 'the clinical potential of profiling tumor cells in bone marrow aspirates', 'e2': ' blood ', 'relation': ' together with', 'condition': 'in metastatic prostate cancer'}, {'e1': 'bone marrow aspirates', 'e2': 'low-frequency serial collection ', 'relation': 'allow for ', 'condition': 'in a prostate cancer clinic'}, {'e1': 'the fraction of positive bone marrow aspirates ', 'e2': 'blood specimens', 'relation': 'are slightly higher than that of ', 'condition': 'in metastatic patients'}, {'e1': 'circulating tumor cells and metastatic tumor cells ', 'e2': 'proportions of androgen receptor-positive and androgen receptor-negative cells and clonal diversity ', 'relation': 'generally correlated in terms of ', 'condition': 'in the paired specimens available'}]"
522,P70P13,"Tumor cell clusters have been described in the blood and bone marrow of patients with metastatic prostate cancer, but here, we provide a detailed description of their prevalence across clinical states. The frequency of patients positive for circulating tumor cell clusters in the metastatic castration-sensitive and metastatic castration-resistant prostate cancer cohorts was higher than previously reported. Novel is our finding of circulating tumor cell clusters in biochemically recurrent prostate cancer patients, which, although rare, were sometimes composed of six or more cells. As circulating clusters have been suggested to have greater metastatic potential than single circulating tumor cells and are linked to poor prognosis for patients who have them, we also evaluated their prognostic significance in metastatic castration-resistant prostate cancer, where the disease is already in a metastatic state. Replicating the analysis from Aceto and colleagues, we confirmed the trend that patients with clusters in the blood at any time, including follow-up samples, had shorter progression-free survival and overall survival than patients with only single circulating tumor cells or no circulating tumor cells at all, but we further extended it to the fraction of cells in clusters in bone marrow aspirate at the time of disease progression, where a significant signal was also detected for both progression-free survival and overall survival. It will be of interest to assess whether a similar association exists for circulating or marrow clusters within the biochemically recurrent prostate cancer and metastatic castration-sensitive prostate cancer cohorts that are actively being followed, for use along PSA doubling time and other clinical factors, to improve determination of risk for metastatic progression and need for treatment.","[{'e1': 'The frequency of patients positive for circulating tumor cell clusters ', 'e2': 'previously reported', 'relation': 'was higher than ', 'condition': 'in the metastatic castration-sensitive cancer cohorts'}, {'e1': 'The frequency of patients positive for circulating tumor cell clusters ', 'e2': 'previously reported', 'relation': 'was higher than ', 'condition': ' in metastatic castration-resistant prostate cancer cohorts'}, {'e1': ' circulating tumor cell clusters', 'e2': 'six or more cells', 'relation': 'were sometimes composed of ', 'condition': 'in biochemically recurrent prostate cancer patients'}, {'e1': ' a significant signal', 'e2': 'for progression-free survival ', 'relation': ' was also detected ', 'condition': 'in bone marrow aspirate at the time of disease progression'}, {'e1': ' a significant signal', 'e2': 'for overall survival', 'relation': ' was also detected ', 'condition': 'in bone marrow aspirate at the time of disease progression'}]"
523,P70P3,"The incidence of tumor cells in bone marrow aspirates increased as the disease advanced: 0% in biochemically recurrent, 26% in newly diagnosed metastatic hormone-naïve, and 39% in metastatic castration-resistant prostate cancer patients, and their number was often higher than in paired blood. Tumor cell detection in metastatic patients' bone marrow aspirates was concordant but 45% more sensitive than using traditional histopathologic interpretation of core bone marrow biopsies. Tumor cell clusters were more prevalent and bigger in bone marrow aspirates than in blood, expressed higher levels of the androgen receptor protein per tumor cell, and were prognostic in metastatic castration-resistant prostate cancer. Moreover, the patterns of genomic copy number variation in single tumor cells in paired blood and bone marrow aspirates showed significant inter- and intrapatient heterogeneity.","[{'e1': 'Tumor cell detection ', 'e2': ' traditional histopathologic interpretation of core bone marrow biopsies', 'relation': 'was 45% more sensitive than using', 'condition': ""in metastatic patients' bone marrow aspirates""}]"
524,P70P4,"Paired analysis of single prostate cancer cells in blood and bone shows promise for clinical application and provides complementary information. The high prevalence and prognostic significance of tumor cell clusters, particularly in bone marrow aspirates, suggest that these structures are key mediators of prostate cancer's metastatic progression.","[{'e1': 'Paired analysis of single prostate cancer cells ', 'e2': 'clinical application ', 'relation': 'shows promise for ', 'condition': 'in blood and bone'}, {'e1': 'Paired analysis of single prostate cancer cells ', 'e2': 'complementary information', 'relation': 'provides ', 'condition': 'in blood and bone'}, {'e1': 'tumor cell clusters ', 'e2': ""prostate cancer's metastatic progression"", 'relation': 'are key mediators of ', 'condition': 'particularly in bone marrow aspirates, '}]"
525,P70P6,"The liquid biopsy approach can deliver single-cell resolution access to the tumor in routine peripheral blood samples through circulating tumor cells. A growing number of studies show that circulating tumor cells have diagnostic, prognostic, and predictive value in a variety of cancer settings. In metastatic castration-resistant prostate cancer, a semiautomated, epithelial cell enrichment and detection-based method has proven useful in prognosticating survival outcomes. Yet, this method and others that recognize circulating tumor cells based on size, density, or epithelial marker expression can miss circulating tumor cell subpopulations, some of which may also be clinically relevant. In contrast to most circulating tumor cell analysis approaches, the high-definition single-cell analysis platform used here allows for a flexible cell identification process, wherein all nucleated cells in a sample are stained and imaged without prior cell population enrichment. This direct analysis approach is designed to quantify and record morphometric parameters such as size and shape and protein expression levels in individual cells and cell clusters, and to provide routine and clinically consistent access to any cell for downstream analysis, including single-cell genomics and proteomics. By characterizing cancer at the single-cell level, we are aiming to link biology with the specific properties of an individual patient's disease.","[{'e1': 'The liquid biopsy approach ', 'e2': 'single-cell resolution access to the tumor ', 'relation': 'can deliver ', 'condition': 'in routine peripheral blood samples through circulating tumor cells'}, {'e1': 'a semiautomated, epithelial cell enrichment and detection-based method', 'e2': 'survival outcomes', 'relation': ' has proven useful in prognosticating ', 'condition': ' In metastatic castration-resistant prostate cancer'}, {'e1': 'This direct analysis approach ', 'e2': 'morphometric parameters such as size and shape and protein expression levels ', 'relation': 'is designed to quantify and record ', 'condition': 'in individual cells and cell clusters'}]"
526,P70P7,"Circulating tumor cells and single-cell high-content analysis may overcome critical limitations of tumor biopsies in dissecting temporal and spatial intratumor heterogeneity in the individual patient. Yet, circulating tumor cells as a population are also heterogeneous, molecularly and in their ability to form metastases, and dynamic, as their presence and composition can change over time and under treatment pressure. As the primary target for metastasis, where tumor cells expand and adapt to therapy, bone is arguably the most relevant organ site to analyze the characteristics and behavior of advanced prostate cancer. We adapted the high-definition single-cell analysis assay to fluid form bone marrow aspirates to discern features most significant to the tumorigenicity and the dynamics of metastatic progression, and to enable repeat comparisons between tumor cells in the circulatory and bone marrow compartments in a clinically applicable manner in prostate cancer. We evaluated and present here the detection rate, organization, androgen receptor expression and distribution, and genomic architecture in tumor cells from peripheral blood and bone marrow aspirates from prostate cancer patients in various stages of progression. Our results demonstrate how the high-definition single-cell analysis assay allows for paired interrogation of two types of liquid biopsies at the single-cell level, providing unique insights into the characteristics of the tumor's circulatory and metastatic components.","[{'e1': 'Circulating tumor cells and single-cell high-content analysis ', 'e2': 'critical limitations of tumor biopsies ', 'relation': 'may overcome ', 'condition': 'in dissecting temporal and spatial intratumor heterogeneity in the individual patient'}, {'e1': ' high-definition single-cell analysis assay ', 'e2': 'paired interrogation of two types of liquid biopsies', 'relation': 'allows for ', 'condition': ' at the single-cell level'}, {'e1': 'genomic architecture in tumor cells ', 'e2': 'prostate cancer patients', 'relation': 'from peripheral blood and bone marrow aspirates from ', 'condition': ' in various stages of progression'}]"
527,P70P8,"Although bone is the most frequent and often only site of clinically detectable metastasis, the patterns of metastatic dissemination in prostate cancer are increasingly recognized as heterogeneous in organization and progressively complex over time. Recent studies demonstrate that tumor clones from distinct metastatic foci are dynamically represented in the blood of patients at a given time and that differences may exist between those in tissue and circulation, especially under the selective pressure of therapy. In this context, methods that allow for serial monitoring of the disease composition not just in the blood as the necessary route for distant metastasis but also in the bone marrow as the most frequent site of metastatic progression and therapy resistance are likely to provide valuable biological and therapeutic insights into the most relevant determinants of such progression. As part of efforts to complement and enhance the relevance and depth of our observations in blood and to develop a technique to serially profile metastatic deposits with potential for clinical application, we decided to expand the combined phenotypic and genetic profiling abilities of our high-definition single-cell analysis platform to bone marrow aspirates in prostate cancer patients.","[{'e1': 'the patterns of metastatic dissemination ', 'e2': 'heterogeneous ', 'relation': 'in prostate cancer are increasingly recognized as ', 'condition': 'in organization and progressively complex over time'}, {'e1': 'tumor clones from distinct metastatic foci ', 'e2': 'the blood of patients ', 'relation': 'are dynamically represented in ', 'condition': 'at a given time'}, {'e1': 'high-definition single-cell analysis platform', 'e2': 'bone marrow aspirates', 'relation': 'was expanded to', 'condition': 'in prostate cancer patients'}]"
528,P70P9,"By profiling specimens across both castration-sensitive and castration-resistant metastatic disease, we were able to estimate a tumor cell detection rate in bone marrow aspirate samples of approximately 25% in metastatic castration-sensitive prostate cancer and 40% in metastatic castration-resistant prostate cancer, which, for metastatic patients, was 45% higher than in corresponding bone marrow biopsies. When tumor cells were found in a bone marrow aspirate, their number often greatly exceeded that in the paired blood, but both the distribution of androgen receptor-expressing cells and the clonality as defined by copy number variation were similar across compartments, supporting that circulating tumor cells often provide an adequate representation of cells in the metastatic deposit. However, our initial observations comparing the subclonal composition between compartments in 3 patients revealed that large inter- and intrapatient differences can exist as well. All three cases differed in how the subclones were distributed between blood and bone, ranging from a single clone in both compartments to parallel clones, where some were shared and others unique to either compartment. Yet, perhaps our most intriguing and novel findings were the frequent cooccurrence of tumor cell clusters in the blood and liquid bone marrow aspirate fractions of individual metastatic patients, their prognostic significance in the subset of metastatic castration-resistant prostate cancer patients, and especially how androgen receptor expression increased with the number of cells in clusters.","[{'e1': 'circulating tumor cells ', 'e2': 'an adequate representation of cells', 'relation': 'often provide ', 'condition': ' in the metastatic deposit.'}]"
529,P71P1,"Prostate cancer management is complicated by extreme disease heterogeneity, which is further limited by availability of prognostic biomarkers. Recognition of prostate cancer as a genetic disease has prompted a focus on the nuclear genome for biomarker discovery, with little attention given to the mitochondrial genome. While it is evident that mitochondrial DNA (mtDNA) mutations are acquired during prostate tumorigenesis, no study has evaluated the prognostic value of mtDNA variation. Here we used next-generation sequencing to interrogate the mitochondrial genomes from prostate tissue biopsies and matched blood of 115 men having undergone a radical prostatectomy for which there was a mean of 107 months clinical follow-up. We identified 74 unique prostate cancer specific somatic mtDNA variants in 50 patients, providing significant expansion to the growing catalog of prostate cancer mtDNA mutations. While no single variant or variant cluster showed recurrence across multiple patients, we observe a significant positive correlation between the total burden of acquired mtDNA variation and elevated Gleason Score at diagnosis and biochemical relapse. We add to accumulating evidence that total acquired genomic burden, rather than specific mtDNA mutations, has diagnostic value. This is the first study to demonstrate the prognostic potential of mtDNA mutational burden in prostate cancer.","[{'e1': '74 unique prostate cancer specific somatic mtDNA variants ', 'e2': 'growing catalog of prostate cancer mtDNA mutations', 'relation': 'providing significant expansion to the ', 'condition': 'in 50 patients'}]"
530,P71P4,"The significance of the mitochondrial genome can be directly attributed to mitochondrial function, in particular the generation of the majority of cellular energy in the form of adenosine triphosphate through oxidative phosphorylation of glucose, as well as significant roles in the regulation of apoptosis and calcium homeostasis. Cells have multiple mitochondria, each containing several copies of the mitochondrial genome. The 16,569 base circular haploid genome encodes for 37 genes; 13 protein coding, 2 ribosomal rRNA and 22 transfer tRNAs. A 10-fold higher mutation rate than nuclear DNA, it is not surprising that mutations in the mtDNA have been associated with several cancers, including prostate cancer. These sporadic variants may become fixed or lost over time, creating a state of heteroplasmy. The assumption is that a variant need to reach a frequency threshold to have an impact on cell function.","[{'e1': 'The significance of the mitochondrial genome ', 'e2': 'mitochondrial function ', 'relation': 'can be directly attributed to ', 'condition': 'through oxidative phosphorylation of glucose'}]"
531,P71P7,"In this study, we contribute 68 novel prostate cancer associated mtDNA mutations to the growing somatic catalog, while confirming six others. Taken together, roughly 3% of the total mitochondrial genome has now been shown to have mutagenic potential during prostate tumourigenesis. Accounting for previous study biases towards the restricted analysis of the hypervariable regions within the control region of mtDNA, the greatest overall impact appears to be within the smaller 1.2 kb non-coding portion of the genome, observing 14 SNVs per kb in our study. We confirm a previously reported bias towards mutational events within the tRNAs, reporting 8.7 SNVs per kb. We predict 32% of our identified mutations to have biological potential, with roughly half present in sufficient frequency to alter mitochondrial function. Further biological studies are required to determine the overall impact of these somatic mutations on energy metabolism, specifically their potential to drive tumor respiration from one of oxidative phosphorylation to aerobic glycolysis, a common cancer phenomenon known as the Warburg effect.","[{'e1': 'roughly 3% of the total mitochondrial genome ', 'e2': ' mutagenic potential ', 'relation': 'has now been shown to have', 'condition': 'during prostate tumourigenesis'}]"
532,P71P8,"The unique properties of mtDNA including its small size, high copy number, susceptibility to mutations and heteroplasmic populations has spearheaded investigations into the clinical significance of somatic mtDNA variation. A recent study suggested that, it is more likely the accumulation of mitochondrial mutations across the entire genome rather than specific mutations that contribute to prostate cancer progression. The latter study showed an association between the mutational load, which is the total number and frequency of mtDNA somatic mutations, and higher Gleason score at diagnosis. We concur that the number and cumulative frequency of SNVs in the mitochondrial genome appears to be an independent predictor for prostate cancer presentation, with significant diagnostic potential for aggressive disease. While we confirm a diagnostic value to the number and frequency of somatic mtDNA SNVs based on a single core interrogation, we do not provide support for the previously reported 3.4 kb mtDNA deletion variant. It should be noted, however, that Mitomics proposes a minimum five-specimen requirement to achieve adequate sensitivity for early prostate cancer detection.","[{'e1': 'the mutational load', 'e2': 'higher Gleason score ', 'relation': 'showed an association with ', 'condition': 'at diagnosis'}]"
533,P71P9,"Historically studies focused on the identification of molecular biomarkers for prostate cancer have lacked prognostic potential. This is the first study, to our knowledge, to investigate the prognostic role of somatic mtDNA in prostate cancer, supported by the availability of extensive long-term clinical follow-up. We demonstrate that an increase in the number of mtDNA somatic SNVs, both the absolute and CVF is significantly correlated to disease relapse and that this prediction appears to improve stand alone Gleason score based risk prediction. The clinical significance of identifying patients prone to relapse has recently been highlighted by the reported benefit from salvage therapy at the earliest opportunity. Associating an increase in number of mtDNA somatic SNVs with both aggressive disease at presentation and poor outcomes, questions whether we observe a limitation to the number of mutagenic events a cell can tolerate. Although we observed a single individual with four SNVs, the upper limit in our study appears to be three mutagenic events. Further cataloging of prostate cancer associated mitochondrial mutations is required not only to determine the spectrum and combination of oncogenic variants, as well as the upper limits for cellular viability, but importantly, to provide significant clinical potential.","[{'e1': 'the first study', 'e2': 'prognostic role of somatic mtDNA ', 'relation': ' to investigate the ', 'condition': 'in prostate cancer'}]"
534,P72P1,"Molecular biomarkers that might help to distinguish between more aggressive and clinically insignificant prostate cancers (PCa) are still urgently needed. Aberrant DNA methylation as a common molecular alteration in PCa seems to be a promising source for such biomarkers. In this study, PITX3 DNA methylation (mPITX3) and its potential role as a prognostic biomarker were investigated. Furthermore, mPITX3 was analyzed in combination with the established PCa methylation biomarker PITX2 (mPITX2).","[{'e1': 'Aberrant DNA methylation ', 'e2': 'source for such biomarkers', 'relation': 'seems to be a promising ', 'condition': ' in PCa'}]"
535,P72P10,"In this study, PITX3 was shown to be aberrantly methylated in prostate carcinomas. PITX3 was hypermethylated in PCa compared to normal adjacent prostate tissue in the training cohort and compared to both normal and benign prostatic hyperplasia in the test study. These findings are in line with previous reports on PITX3 methylation in breast carcinoma.","[{'e1': 'PITX3 ', 'e2': 'aberrantly methylated ', 'relation': 'was shown to be ', 'condition': 'in prostate carcinomas'}]"
536,P72P11,"Furthermore, carcinomatous PITX3 hypermethylation was significantly associated with established clinicopathologic parameters characteristic of PCa. In detail, high ISUP Gleason grading group, advanced tumor stages, and high preoperative PSA values were related to high PITX3 methylation in both cohorts. In addition, PITX3 methylation correlated with a molecular AR activity score as obtained from TCGA Research Network, which was only available for the training cohort. An association with the ERG fusion protein or ERG protein expression could not be determined. Recently, dysregulation of PITX3 methylation has been linked to the environmental burden of xenoestrogens. In this respect, PITX3 methylation may have an exceptional position among prognostic biomarkers. Of note, PITX3 methylation served as a prognostic biomarker for BCR in both the training and validation cohort of radical prostatectomy patients. In Kaplan-Meier analysis, high PITX3 methylation defined by an optimized cutoff for both patient groups was associated with a shorter BCR-free survival in the training and validation cohort. As a limiting condition, however, the follow-up period was shorter in the training cohort compared to the validation cohort, and the training cohort comprised significantly more high-grade carcinomas with an advanced stage and associated with earlier BCR. In the validation cohort, PITX3 methylation succeeded as a prognostic factor dichotomized by an optimized cutoff and as a continuous variable in the univariate Cox proportional hazards analysis.","[{'e1': 'PITX3 methylation ', 'e2': 'BCR ', 'relation': 'served as a prognostic biomarker for ', 'condition': 'in both the training and validation cohort of radical prostatectomy patients'}, {'e1': 'high PITX3 methylation ', 'e2': 'a shorter BCR-free survival ', 'relation': 'associated with ', 'condition': 'in the training and validation cohort'}, {'e1': 'PITX3 methylation', 'e2': 'a prognostic factor dichotomized by an optimized cutoff ', 'relation': ' succeeded as ', 'condition': 'In the validation cohort'}, {'e1': 'PITX3 methylation', 'e2': 'continuous variable ', 'relation': ' succeeded as a ', 'condition': 'in the univariate Cox proportional hazards analysis.'}]"
537,P72P12,"In consideration of the fact that several recent studies have reported on a striking prognostic power of gene methylation of PITX2, a close relative of PITX3, a combined analysis of PITX2 and PITX3 promoter methylation, was performed. Thereby, we intended to investigate possible interactions to compensate for gene methylation in either PITX member. Combined analysis of PITX2 and PITX3 promoter methylation revealed that low methylation in both genes was associated with favorable courses of disease in each cohort. Vice versa, patients with hypermethylated PITX2 and PITX3 promoters presented with the shortest BCR-free survival intervals after radical prostatectomy. Intermediate BRC-free survival intervals were observed in patients with low gene methylation in one PITX member and high methylation in the other PITX members. In respect thereof, we conclude that the analysis of PITX3 gene methylation adds to the prognostic information obtained from PITX2 analysis, suggesting that, in contrast to their overlapping functions in human development, they play a distinct role in the genesis and progression of PCa. This issue further needs to be confirmed in larger studies in which patient numbers allow for multivariate analysis. Furthermore, the prognostic value should be analyzed with regard to more clinically relevant endpoints, i.e., prostate cancer-specific survival, which unfortunately was not available for the present analyses.","[{'e1': 'low methylation ', 'e2': 'favorable courses of disease in each cohort', 'relation': 'was associated with ', 'condition': ' in both genes '}, {'e1': 'patients with hypermethylated PITX2 and PITX3 promoters', 'e2': 'shortest BCR-free survival intervals ', 'relation': ' presented with the ', 'condition': 'after radical prostatectomy'}]"
538,P72P3,"In PCa tissue, mPITX3 was increased significantly compared to normal and benign hyperplastic tissue. In univariate Cox proportional hazards analyses, mPITX3 showed a significant prognostic value for BCR (training cohort: hazard ratio (HR) = 1.83 (95 % CI 1.07–3.11), p = 0.027; validation cohort: HR = 2.56 (95 % CI 1.44–4.54), p = 0.001). A combined evaluation with PITX2 methylation further revealed that hypermethylation of a single PITX gene member (either PITX2 or PITX3) identifies an intermediate risk group.","[{'e1': 'mPITX3 ', 'e2': 'normal and benign hyperplastic tissue', 'relation': 'was increased significantly compared to ', 'condition': 'In PCa tissue'}, {'e1': ' mPITX3 ', 'e2': ' BCR ', 'relation': 'showed a significant prognostic value for', 'condition': 'in univariate Cox proportional hazards analyses'}]"
539,P72P6,"As potential biomarkers, epigenetic modifications such as hyper- or hypomethylation of tumor-related genes have lately emerged as one of the key alterations in cancer development. Aberrant patterns of methylation have aroused interest in the molecular subclassification of urologic tumors and might potentially serve as prognostic and predictive biomarkers in PCa. Furthermore, DNA is a highly robust cellular element that can be extracted reliably from different materials, e.g., fresh tissue, formalin-fixed paraffin-embedded tissue (FFPET), and body fluids.","[{'e1': 'epigenetic modifications ', 'e2': 'one of the key alterations', 'relation': 'have lately emerged as ', 'condition': ' in cancer development.'}, {'e1': 'Aberrant patterns of methylation ', 'e2': 'prognostic and predictive biomarkers ', 'relation': 'might potentially serve as ', 'condition': 'in PCa'}]"
540,P72P7,"Methylation of the paired-like homeodomain transcription factor 2 (PITX2) has been successfully proven a powerful prognostic biomarker in several cancer entities such as lung cancer, hormone-receptor-negative breast cancer, and PCa. PITX2 is initiated by Wnt/β-catenin and is involved in the control of cell proliferation. PITX2 regulates the expression of the androgen receptor (AR) and insulin-like growth factor (IGF) receptor genes, leading to the regulation of signaling pathways involving AR and IGF during PCa progression.","[{'e1': 'Methylation of the paired-like homeodomain transcription factor 2 (PITX2) ', 'e2': 'powerful prognostic biomarker ', 'relation': 'has been successfully proven a ', 'condition': 'in several cancer entities such as lung cancer'}, {'e1': 'Methylation of the paired-like homeodomain transcription factor 2 (PITX2) ', 'e2': 'powerful prognostic biomarker ', 'relation': 'has been successfully proven a ', 'condition': 'in several cancer entities such as hormone-receptor-negative breast cancer'}, {'e1': 'Methylation of the paired-like homeodomain transcription factor 2 (PITX2) ', 'e2': 'powerful prognostic biomarker ', 'relation': 'has been successfully proven a ', 'condition': 'in several cancer entities such asPCa'}, {'e1': 'PITX2 ', 'e2': 'regulation of signaling pathways involving AR and IGF ', 'relation': 'leads to the ', 'condition': 'during PCa progression.'}]"
541,P72P8,"The paired-like homeodomain transcription factor 3 or pituitary homeobox 3 (PITX3) is a transcription factor belonging to the same protein family as PITX2. PITX3 has been shown to be transiently expressed in the eye lens and skeletal muscle during embryogenesis. Very recently, it has been reported that exposure to environmental xenoestrogens may lead to neonatal DNA methylation re-programing effects in the prostate including dysregulation of PITX3 methylation. This may potentially foster carcinogenesis. Moreover, PITX3 has previously been found to be aberrantly methylated in breast cancer patients.","[{'e1': 'PITX3 ', 'e2': 'transiently expressed ', 'relation': 'has been shown to be ', 'condition': 'in the eye lens and skeletal muscle '}, {'e1': 'PITX3 ', 'e2': 'in the eye lens and skeletal muscle ', 'relation': 'has been shown to be transiently expressed ', 'condition': 'during embryogenesis'}, {'e1': ' exposure to environmental xenoestrogens ', 'e2': 'DNA methylation re-programing effects ', 'relation': 'may lead to neonatal ', 'condition': 'in the prostate including dysregulation of PITX3 methylation'}, {'e1': 'PITX3 ', 'e2': ' aberrantly methylated', 'relation': 'has previously been found to be', 'condition': ' in breast cancer patients.'}]"
542,P72P9,These findings prompted us to investigate PITX3 promoter methylation in PCa in a publically available dataset from The Cancer Genome Atlas (TCGA) (training cohort) and an independent primary PCa patient cohort from the University Hospital Bonn (validation cohort).,"[{'e1': 'These findings', 'e2': 'PITX3 promoter methylation ', 'relation': ' prompted us to investigate ', 'condition': 'in PCa'}]"
543,P73P10,"The finding that prostate cancers with ductal histologic features may be enriched for somatic hypermutation is intriguing; however, our small sample size limits our ability to draw definitive conclusions regarding this genotype-histologic phenotype relationship. If this finding is confirmed, however, the presence of ductal adenocarcinoma histology could be a means to prioritize patients for additional studies to assess mutational burden, which may have clinical implications, as hypermutation appears to predict for response to immune checkpoint blockade in several cancer types, including early signals in prostate cancer. Future efforts to define the landscape of genomic alterations in patients with this prostate cancer variant will likely require multi-institutional studies. Such studies may facilitate the promise and rapid completion of precision oncology approaches for targeting this molecular subset of prostate cancer.","[{'e1': 'hypermutation ', 'e2': 'response to immune checkpoint blockade ', 'relation': 'appears to predict for ', 'condition': 'in several cancer types, including early signals in prostate cancer.'}]"
544,P73P2,"Precision oncology entails therapeutic decision-making on the basis of an individual patient’s molecular tumor profile. To that end, it is imperative to develop strategies to rapidly identify clinically relevant patient subgroups. While next-generation sequencing technologies have greatly advanced molecular classification, they are not routinely used for prostate cancer and may be costly. Because histological variants can correlate with genomic alterations in other malignancies, we hypothesized that distinct prostate cancer histologies may also associate with underlying molecular aberrations – allowing for the rapid identification of patients for further screening. In this study, we sought to determine if ductal prostate cancer (dPC) was associated with clinically actionable molecular features.","[{'e1': 'histological variants ', 'e2': 'genomic alterations ', 'relation': 'can correlate with ', 'condition': 'in other malignancies'}]"
545,P73P4,"While the more aggressive clinical course associated with dPC has been well documented, little is known about the molecular features underlying this histologic subtype. Studies using fluorescence in situ hybridization have reported the prevalence of TMPRSS2:ERG fusions in ductal cases to range from approximately 10–50%, which is not substantially different than typical acinar carcinomas. Otherwise, gene expression profiling studies reveal extensive similarities between ductal and acinar adenocarcinomas. In one study comparing the transcriptional profile of eight ductal tumors to 11 acinar adenocarcinomas, differences in gene expression profiles encompassed only 25 genes.","[{'e1': 'prevalence of TMPRSS2:ERG fusions ', 'e2': 'approximately 10–50%', 'relation': 'to range from ', 'condition': 'in ductal cases'}]"
546,P73P8,"Determining which patients have hypermutated prostate tumors may have important implications for future precision oncology trials, as mutational burden has been shown to correlate with response to immune checkpoint blockade in several tumor types (e.g. anti-CTLA4, anti-PD1, anti-PDL1). Although objective responses to immune checkpoint inhibition have initially been generally disappointing in patients with prostate cancer, most have a relatively low mutational load. A recent Phase II study testing pembrolizumab (anti-PD1 therapy) in patients with metastatic colorectal carcinoma with and without MMR deficiency reported that 40% of hypermutated colorectal cancer patients had an immune-related objective response compared to 0% of patients without MSI-high tumors. Moreover, a 50% response rate to pembrolizumab in hypermutated non-colorectal gastrointestinal malignancies has been observed – supporting the hypothesis that mutational load may be a predictive biomarker for response to immune checkpoint blockade in prostate cancer. The observation that one of the hypermutated patients followed in our clinic had a dramatic response to anti-PD1 therapy in spite of being heavily pretreated further bolsters the hypothesis that hypermutation may be predictive of response to PD1/PDL1 pathway inhibition.","[{'e1': 'mutational burden ', 'e2': 'response to immune checkpoint blockade ', 'relation': 'has been shown to correlate with ', 'condition': 'in several tumor types'}]"
547,P73P9,"Consistent with our prior observations, we found that somatic loss-of-function mutations in MSH2 and MSH6 were the primary cause of microsatellite instability in patients with prostate cancer. This is in contrast to colorectal cancer where hypermutation has been found to be associated with epigenetic silencing of MLH1, which occurs in nearly 2/3 of the cases. Interestingly, the tumor of Subject #2 showed evidence of MSH2 inversion without clear evidence of hypermutation or MSI. Whether the MSH2 loss-of-function alteration represents an early event and hypermutation is a later consequence in the disease course or follows selective pressures of treatment will need to be further examined. Given that the mechanisms underlying prostate cancer hypermutation appear distinct from colorectal cancer, patterns of MSI may also be divergent and a tailored approach to MSI testing of prostate cancer may be needed. However, our findings suggest that ductal histology may be a cue to investigate further for evidence of MMR deficiency and hypermutation.","[{'e1': 'somatic loss-of-function mutations in MSH2 and MSH6', 'e2': 'microsatellite instability ', 'relation': ' were the primary cause of ', 'condition': 'in patients with prostate cancer'}, {'e1': 'hypermutation ', 'e2': 'epigenetic silencing of MLH1', 'relation': 'has been found to be associated with ', 'condition': 'in colorectal cancer'}]"
548,P74P1,"Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM+/CK+) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a “surrogate” of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well.","[{'e1': 'circulating tumor cells (CTC) ', 'e2': 'prognosis and response to therapy ', 'relation': 'can predict ', 'condition': 'in metastatic breast'}, {'e1': 'circulating tumor cells (CTC) ', 'e2': 'prognosis and response to therapy ', 'relation': 'can predict ', 'condition': 'in prostate cancer'}, {'e1': 'circulating tumor cells (CTC) ', 'e2': 'prognosis and response to therapy ', 'relation': 'can predict ', 'condition': 'in colon cancer'}]"
549,P74P10,"Additionally, we have shown that CTC in EMT can predict OS of patients from the time of metastasis occurrence, while the trial SWOG S0500 has suggested that patients in which CTC are not reduced after chemotherapy may represent a group of patients resistant to common chemotherapy. It would be therefore interesting to genetically and transcriptionally characterize CTC in EMT in drug-resistant patients to determine a putative sensitivity to alternative drugs.","[{'e1': 'CTC ', 'e2': 'OS of patients from the time of metastasis occurrence', 'relation': 'can predict ', 'condition': 'in EMT'}, {'e1': 'CTC ', 'e2': 'a group of patients resistant to common chemotherapy', 'relation': 'may represent ', 'condition': 'after chemotherapy'}]"
550,P74P2,"An effective anticancer treatment must be able to eradicate all tumor cells; additionally, recent therapeutic advances in oncology recognize a patient-to-patient variability in the mutational status of tumors, the so-called interpatient heterogeneity. This latter dictates the choice of targeted drugs. However, tumors are evolving entities and genetic heterogeneity has been detected analyzing different regions of the same tumor, or comparing the primary tumor with subsequent recurrences and metastases. Therefore, it has been hypothesized that the success of personalized treatments greatly depends on the capability to capture and monitor tumor heterogeneity over time and to consequently modulate therapies.","[{'e1': 'recent therapeutic advances in oncology ', 'e2': 'a patient-to-patient variability ', 'relation': 'recognize ', 'condition': 'in the mutational status of tumors'}]"
551,P74P4,"Therefore, great interest is now focused on the opportunity to monitor tumor genome evolution by the characterization of cell-free circulating tumor DNA, circulating tumor-derived exosomes and circulating tumor cells (CTC). This approach, known as “liquid biopsy”, requires a simple blood draw, a minimally invasive practice that can be easily repeated over time, thus ensuring a constantly open window on the genomic landscape of the tumor. However, despite the ease of the sampling procedure, cell-free circulating tumor DNA, exosomes and CTC are extremely rare events dispersed in the blood and their identification, quantification and analyses have requested and favored the development of multiple new technologies.","[{'e1': 'exosomes and CTC', 'e2': 'extremely rare events dispersed ', 'relation': ' are ', 'condition': 'in the blood and their identification'}]"
552,P74P8,"Considering the genomic landscape, comprehensive single cell sequencing strategies have confirmed that CTC, at least in some clinical settings, are able to capture tumor heterogeneity and can allow a real-time monitoring of the appearance of drug-resistant clones, opening the way to use CTC as a liquid biopsy. Although a number of technical challenges still lie ahead before single cells sequencing techniques can be widely adopted by researchers and clinicians, they represent an invaluable opportunity for a personalized approach. Conversely, the detection of known-drug related molecules on CTC is already under evaluation in clinical trials.","[{'e1': 'CTC ', 'e2': 'a real-time monitoring of the appearance of drug-resistant clones', 'relation': ' can allow ', 'condition': ' in some clinical settings'}]"
553,P74P9,"Interestingly, it was shown that CTC could express EMT markers, as well as stem cell markers, and that this correlated with prognosis and drug resistance. EMT is a process that can induce in cancer cells many of the functional properties responsible of tumor aggressiveness, such as invasiveness, stemness, metabolic reprogramming and drug-resistance. Moreover, the pathways of these phenomena are overlapping and can be druggable. Indeed, several trials are now evaluating the ability of drugs possibly interfering with EMT and stemness to revert the drug-resistance to commonly used drugs.","[{'e1': 'EMT ', 'e2': 'many of the functional properties responsible of tumor aggressiveness', 'relation': 'is a process that can induce ', 'condition': 'in cancer cells'}]"
554,P75P1,"Evidence supports the upregulation of MUC1 in prostate cancer (PC). However, this has not been thoroughly investigated. We report here an association of MUC1 upregulation with PC metastasis and the development of castration resistant PC (CRPC). MUC1 expression was specifically increased in DU145 cell-derived PC stem-like cells (PCSLCs) in comparison to their non-PCSLCs counterparts. While immunohistochemistry staining of 34 primary PCs revealed variability in MUC1 expression, Nanostring technology demonstrated elevated MUC1 mRNA levels in 4 of 7 PCs compared to their normal matched tissues. By analyzing MUC1 mRNA levels and gene copy number (GCN) using the Oncomine database, elevations in MUC1 mRNA in 82 metastases versus 280 primary PCs and in MUC1 GCN in 37 metastases over 181 primary tumors were demonstrated. Analysis of genomic datasets within cBioPortal revealed increases in MUC1 GCN in 2% of primary PCs, 6% of metastatic PCs, and 33% of CRPCs; in comparison, the respective increase in androgen receptor (AR) GCN was 1%, 63%, and 56%, revealing a specific increase in MUC1 GCN for CRPC. Furthermore, a 25-gene MUC1 network was amplified in 52% of CRPCs compared to 69% of CRPCs displaying increases in an AR co-regulator group. While genomic alterations in the MUC1 network largely overlap with those in the AR group, 18 CRPCs, 66.7% being neuroendocrine PC, showed genomic alterations only in the MUC1 network. Moreover, genomic alterations in the MUC1 network correlated with PC relapse. Collectively, our observations suggest a combination therapy involving MUC1-based immunotherapy and androgen deprivation.","[{'e1': 'MUC1 expression ', 'e2': 'DU145 cell-derived PC stem-like cells (PCSLCs) ', 'relation': 'was specifically increased in ', 'condition': 'in comparison to their non-PCSLCs counterparts'}, {'e1': 'Nanostring technology ', 'e2': 'elevated MUC1 mRNA levels', 'relation': 'demonstrated ', 'condition': ' in 4 of 7 PCs compared to their normal matched tissues'}]"
555,P75P12,"Considering the well-established associations of genomic alterations in the AR and its co-activator genes with CRPC, it is confirmative that respective aberrations in the MUC1 network are as specific as those in the AR in identifying CRPC. This concept needs to be further examined. Nonetheless, it is rather intriguing that genomic alterations in the MUC1 network and AR largely overlap, indicating a positive regulation between AR and MUC1. However, current evidence supports the opposite possibility of mutual inhibition; this negative feedback may contribute to the MUC1 network’s unique genomic changes in NEPCs, suggesting MUC1’s contribution to the generation of NEPC during ADT.","[{'e1': 'aberrations in the MUC1 network ', 'e2': 'those in the AR ', 'relation': 'are as specific as ', 'condition': 'in identifying CRPC'}, {'e1': 'negative feedback ', 'e2': 'the MUC1 network’s unique genomic changes', 'relation': 'may contribute to ', 'condition': ' in NEPCs'}, {'e1': 'MUC1', 'e2': 'of NEPC ', 'relation': ' contributes to the generation ', 'condition': 'during ADT.'}]"
556,P75P2,"Prostate cancer (PC) is the most prevalent male-specific cancer in the developed world. PC progresses from high grade prostatic intra-epithelial neoplasia, to local carcinoma, to metastatic disease with bone as the preferential site. Localized tumors can be effectively managed through a variety of approaches, including watchful waiting, surgical removal, and radiation. In contrast, options for patients with metastatic PC remain limited. Androgen deprivation therapy (ADT), a strategy that was pioneered by Charles Huggins in the 1940s, remains the standard of care in these patients. However, the treatment is only palliative, as resistant tumors in the form of castration resistant PC inevitably arise. Until recently, these patients were commonly treated with docetaxel-based chemotherapy. Cumulative research efforts have revealed the dependency of androgen receptor signaling despite androgen deprivation for a large proportion of CRPCs, which led to the recent development of abiraterone and enzalutamide for treatment. Additionally, the cell-based vaccine Sipuleucel T has recently become available, a therapy that depends on tumor associated antigens.","[{'e1': 'Prostate cancer (PC) ', 'e2': 'male-specific cancer ', 'relation': 'is the most prevalent ', 'condition': 'in the developed world'}]"
557,P75P8,"Our observed upregulation of MUC1 in PCSLCs suggests a mechanism underlying MUC1 overexpression in PC. It is becoming clearer that the plasticity of cancer stem cells is critical in cancer evolution in response to endogenous and exogenous selective pressures such as therapies. This plasticity likely contributes to the acquisition of new properties that drive cancer metastasis and development of therapeutic resistance. In this regard, PCSC-associated plasticity may contribute to MUC1 upregulation. In support of this possibility, we have recently reported a new PC metastatic factor contactin 1 that was also derived from PCSLCs. In a similar manner, PCSC-derived MUC1 may be specifically important for metastatic progression, considering genomic amplification in the MUC1 gene is an infrequent event in metastatic PCs.","[{'e1': 'genomic amplification ', 'e2': 'infrequent event ', 'relation': 'in the MUC1 gene is an ', 'condition': 'in metastatic PCs.'}]"
558,P75P9,"In CRPC however, genomic amplification is likely a major mechanism underlying MUC1 upregulation. It is likely that androgen deprivation is a contributing factor to MUC1 gene amplification in CRPC. This concept is supported by the importance of persistent AR signalling in CRPC development and in promoting genomic instability. Additionally, this concept is also in line with the observed concordance between AR gene amplification and MUC1 gene copy number increases in CRPC. However, the genomic amplifications which occur in MUC1 and its gene network are not merely a side effect of AR signalling-caused genomic instability, which can be reflected by the independent genomic alterations between the MUC1 network and the AR groups.","[{'e1': ' androgen deprivation', 'e2': 'MUC1 gene amplification ', 'relation': ' is a contributing factor to ', 'condition': 'in CRPC'}, {'e1': ' genomic amplification ', 'e2': 'MUC1 upregulation', 'relation': 'is likely a major mechanism underlying ', 'condition': 'In CRPC'}]"
559,P76P10,"Aberrant DNA methylation of certain loci has been reported to play a major role in carcinogenesis. Such epigenetic modifications have further been shown to be a robust and reliable diagnostic tool, therefore representing a promising source for cancer biomarkers. We have very recently shown that promoter methylation of the immune checkpoint receptor PD-1 is an independent prognostic biomarker for biochemical recurrence-free survival in PCa patients following radical prostatectomy. So far, no data are available on the role of PD-L1 promoter methylation in PCa. The aim of this study therefore was to quantify PD-L1 DNA methylation in prostate tissue samples and to evaluate its potential as a biomarker in PCa.","[{'e1': 'Aberrant DNA methylation of certain loci ', 'e2': 'major role ', 'relation': 'has been reported to play a ', 'condition': 'in carcinogenesis'}]"
560,P76P11,"DNA methylation of promoter regions is often associated with epigenetic silencing. In normal tissue around 80% of CpGs are methylated and mainly CpG islands in promoter regions of active genes are hypomethylated. In cancer there is a shift in the pattern of DNA methylation towards a global hypomethylation, whereas certain CpGs, often in promoter regions of tumor suppressor genes, are thought to become hypermethylated. Nevertheless, recent publications show that the aberrant DNA methylation, especially in cancer, is much more complex. In the present study, five Illumina Infinium HumanMethylation450 BeadChip beads taken from the TCGA dataset and located in the promoter region of the PD-L1 gene were analyzed. In this training cohort, mPD-L1 levels were increased significantly in PCa compared to normal tissue, indicating that PD-L1 might be differentially methylated in prostatic malignancies. Further investigations revealed that two of the five examined beads showed a significant correlation of mPD-L1 with BCR in univariate Cox proportional hazards analysis and Kaplan-Meier analysis. Interestingly, differential methylation was found in the border regions and not the centre of the CpG-dense promoter area. One of the two beads further showed an inverse correlation with PD-L1 mRNA expression and an association with prognostic clinicopathological variables including the ISUP grading group, pT, pre-surgical prostate-specific antigen, resection margin, and ERG status.","[{'e1': 'certain CpGs ', 'e2': 'hypermethylated', 'relation': 'are thought to become ', 'condition': ' in promoter regions of tumor suppressor genes'}, {'e1': 'mPD-L1 levels', 'e2': 'in PCa', 'relation': ' were increased significantly ', 'condition': ' compared to normal tissue'}, {'e1': 'PD-L1 ', 'e2': 'differentially methylated ', 'relation': 'might be ', 'condition': 'in prostatic malignancies'}, {'e1': 'two of the five examined beads ', 'e2': 'mPD-L1 with BCR ', 'relation': 'showed a significant correlation of ', 'condition': 'in univariate Cox proportional hazards analysis and Kaplan-Meier analysis'}]"
561,P76P12,"In order to validate these findings with an additional technology in an independent cohort, a quantitative methylation qPCR assay was designed within the region of the best performing bead. In this validation cohort, high PD-L1 DNA methylation, analyzed as a continuous variable and as a dichotomized variable using an optimized cut-off, was significantly associated with an increased risk for BCR in patients in univariate Cox proportional hazards analysis and its prognostic value was further confirmed by Kaplan-Meier analysis.","[{'e1': 'high PD-L1 DNA methylation ', 'e2': 'an increased risk for BCR in patients ', 'relation': 'was significantly associated with ', 'condition': 'in univariate Cox proportional hazards analysis'}]"
562,P76P13,"Surprisingly, our study revealed no inverse correlation of PD-L1 promoter methylation and protein expression in PCa. This may point at a complex post-transcriptional and post-translational regulation of PD-L1. According to our findings, mPD-L1 is inversely correlated with mRNA transcription and associated with miR as a cellular component, which modify the downstream processing of PD-L1 mRNA. Differential expression of miR may therefore potentially interfere with the linear translation of PD-L1 mRNA into PD-L1 protein. Thus, further studies are warranted to unravel the complex interplay between DNA methylation and protein expression in PCa. In addition, post-translational modifications which affect the stability of the protein and in turn alter the affinity of the anti-PD-L1 antibody to membranous PD-L1 might further be causative for ostensibly conflicting results. When combining PD-L1 protein expression and methylation, however, both parameters added independent prognostic information, suggesting that PD-L1 methylation might be a valuable companion biomarker in addition to immunohistochemistry. We would therefore strongly recommend the integration of its analysis in running clinical trials.","[{'e1': 'complex interplay ', 'e2': 'DNA methylation and protein expression', 'relation': 'between ', 'condition': ' in PCa'}]"
563,P76P2,"In the training cohort, normal tissue showed significantly lower levels of mPD-L1 compared to tumor tissue. High mPD-L1 in PCa was associated with biochemical recurrence (BCR) in univariate Cox proportional hazards and Kaplan-Meier analyses. These results were corroborated in an independent validation cohort in univariate Cox and Kaplan-Meier analyses. Although mPD-L1 and PD-L1 protein expression did not correlate in the validation cohort, both parameters added significant prognostic information in bivariate Cox analysis.","[{'e1': 'High mPD-L1 in PCa ', 'e2': ' biochemical recurrence (BCR) ', 'relation': 'was associated with', 'condition': 'in univariate Cox proportional hazards '}, {'e1': 'High mPD-L1 in PCa ', 'e2': ' biochemical recurrence (BCR) ', 'relation': 'was associated with', 'condition': 'in Kaplan-Meier analyses'}, {'e1': 'mPD-L1 and PD-L1 protein expression', 'e2': 'significant prognostic information ', 'relation': ' added ', 'condition': 'in bivariate Cox analysis.'}]"
564,P76P4,"mPD-L1 is a promising biomarker for the risk stratification of PCa patients and might offer additional relevant prognostic information to the implemented clinical parameters, particularly in the setting of immune checkpoint inhibition.","[{'e1': 'mPD-L1 ', 'e2': 'additional relevant prognostic information to the implemented clinical parameters', 'relation': 'might offer ', 'condition': 'particularly in the setting of immune checkpoint inhibition.'}]"
565,P76P5,"Recently, the blockade of the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling pathway, either with antibodies against the receptor PD-1 or its ligand PD-L1, has shown promising results in several advanced cancers, e.g. malignant melanoma, non-small cell lung cancer, bladder cancer, head and neck cancer, and renal cell cancer. While the activation of the PD-1/PD-L1 pathway allows for the tumor to successfully elude the host’s immune system via T-cell exhaustion, a therapy strategically targeting the PD-1/PD-L1 pathway seems to promote the immune response against the tumor. Immunohistochemically detected PD-L1 expression has further been reported to be a predictive biomarker for the treatment with anti-PD-1/PD-L1 treatment.","[{'e1': 'the blockade of the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling pathway ', 'e2': 'promising results ', 'relation': 'has shown ', 'condition': 'in several advanced cancers'}]"
566,P76P7,"The epigenetic mechanism of DNA methylation plays a key role in several fundamental biological processes, e.g. development, cell differentiation, and gene silencing. Furthermore, DNA methylation is often deregulated in human malignancies, suggesting that aberrantly methylated loci might be a valuable source for biomarkers. As DNA methylation can also be robustly quantified in specimens with limited DNA abundance or formalin-fixed paraffin-embedded tissue, in which DNA is highly degraded, methylation-based biomarkers prove to be promising diagnostic tools for clinical routine. So far, various DNA methylation biomarkers have been successfully applied in a clinical setting. The short stature homeobox 2 and septin 9, for instance, are employed as diagnostic and screening tools for the detection of lung cancer and colorectal cancer. In addition, promoter methylation of the O-6-methylguanine-DNA methyltransferase has been shown to be predictive of response to alkylating agents in glioblastoma.","[{'e1': 'DNA methylation ', 'e2': 'deregulated ', 'relation': 'is often ', 'condition': 'in human malignancies'}, {'e1': ' DNA methylation ', 'e2': 'robustly quantified ', 'relation': 'can also be ', 'condition': 'in specimens with limited DNA abundance or formalin-fixed paraffin-embedded tissue'}, {'e1': 'The short stature homeobox 2 and septin 9 ', 'e2': 'diagnostic and screening tools ', 'relation': 'are employed as ', 'condition': 'for the detection of lung cancer and colorectal cancer'}, {'e1': 'promoter methylation of the O-6-methylguanine-DNA methyltransferase ', 'e2': 'response to alkylating agents', 'relation': 'has been shown to be predictive of ', 'condition': ' in glioblastoma.'}]"
567,P76P8,We have very recently shown that promoter methylation of the immune checkpoint receptor PD-1 is an independent prognostic biomarker for biochemical recurrence-free survival in PCa patients following radical prostatectomy. The aim of the present study was to quantify PD-L1 DNA methylation in prostate tissue samples and to evaluate its potential role as a prognostic biomarker in PCa.,"[{'e1': 'promoter methylation of the immune checkpoint receptor PD-1', 'e2': 'independent prognostic biomarker for biochemical recurrence-free survival ', 'relation': ' is an ', 'condition': 'in PCa patients following radical prostatectomy'}, {'e1': 'The aim of the present study ', 'e2': 'PD-L1 DNA methylation ', 'relation': 'was to quantify ', 'condition': 'in prostate tissue samples '}, {'e1': 'The aim of the present study ', 'e2': 'its potential role as a prognostic biomarker ', 'relation': 'was to evaluate ', 'condition': 'in PCa.'}]"
568,P76P9,"Targeting the immune checkpoint pathway PD-1/PD-L1 has emerged as a promising therapy providing significant clinical activity and durable benefits with minimal toxicities in several solid tumors. The rapid development and approval of PD-1/PD-L1 inhibitors has generated an urgent need for predictive biomarkers assisting the selection of patients most likely to respond to therapy. Several clinical trials have suggested immunohistochemically detected PD-L1 expression as a predictive biomarker for the treatment with anti-PD-1/PD-L1 inhibitors. The use of PD-L1 immunohistochemistry as a predictive biomarker, however, is confounded by multiple unresolved issues such as differing antibodies and scoring cut-offs, tissue preparation, as well as interlaboratory and interobserver variability.","[{'e1': 'Targeting the immune checkpoint pathway PD-1/PD-L1 ', 'e2': 'a promising therapy providing significant clinical activity and durable benefits with minimal toxicities ', 'relation': 'has emerged as ', 'condition': 'in several solid tumors'}]"
569,P77P1,"Biomarkers that facilitate the prediction of disease recurrence in prostate cancer (PCa) may enable physicians to personalize treatment for individual patients. In the current study, PD-1 (PDCD1) promoter methylation was assessed in a cohort of 498 PCa patients included in The Cancer Genome Atlas (TCGA) and a second cohort of 300 PCa cases treated at the University Hospital of Bonn. In the TCGA cohort, the PD-1 promoter was significantly hypermethylated in carcinomas versus normal prostatic epithelium and PD-1 methylation inversely correlated with PD-1 mRNA expression in PCa. In both cohorts, PD-1 methylation significantly correlated with preoperative prostate specific antigen (PSA). In univariate Cox Proportional Hazard analysis, PD-1 methylation served as a significant prognostic factor for biochemical recurrence (BCR)-free survival in the TCGA cohort. In multivariate analysis, PD-1 methylation was shown to add significant independent prognostic information adjunct to pathologic tumor category and Gleason grading group. PD-1 promoter methylation analyses could thus potentially aid the identification of patients which might benefit from adjuvant treatment after radical prostatectomy. Moreover, our data suggest an intrinsic role of PD-1 in PCa carcinogenesis and disease progression, which needs to be addressed in future studies.","[{'e1': 'Biomarkers that facilitate the prediction of disease recurrence ', 'e2': 'physicians to personalize treatment for individual patients', 'relation': 'may enable ', 'condition': 'in prostate cancer (PCa) '}, {'e1': 'PD-1 methylation ', 'e2': 'PD-1 mRNA expression', 'relation': 'inversely correlated with ', 'condition': ' in PCa'}, {'e1': 'PD-1 methylation ', 'e2': 'preoperative prostate specific antigen (PSA)', 'relation': 'significantly correlated with ', 'condition': 'In both cohorts'}, {'e1': 'PD-1 methylation', 'e2': ' significant prognostic factor for biochemical recurrence (BCR)-free survival ', 'relation': ' served as a', 'condition': 'In univariate Cox Proportional Hazard analysis'}, {'e1': 'PD-1 methylation', 'e2': ' significant prognostic factor for biochemical recurrence (BCR)-free survival ', 'relation': ' served as a', 'condition': 'in the TCGA cohort'}, {'e1': 'PD-1 methylation ', 'e2': 'significant independent prognostic information adjunct to pathologic tumor category and Gleason grading group', 'relation': 'was shown to add ', 'condition': ' In multivariate analysis'}, {'e1': 'PD-1 promoter methylation analyses ', 'e2': 'the identification of patients which might benefit from adjuvant treatment', 'relation': 'could thus potentially aid ', 'condition': ' after radical prostatectomy'}]"
570,P77P3,"Recently, Gevensleben et al. have shown that the PD-1 receptor ligand PD-L1 is differentially expressed among primary PCa patients. In two large independent cohorts, high PD-L1 expression was significantly associated with adverse outcome. While PD-L1 expression has been recognized in various types of cancers, PD-1 receptor, also known as CD279 and PDCD1, is an immune inhibitory receptor belonging to the extended CD28/CTLA-4 family that is stably expressed on T cells which are exposed to a chronic antigen. PD-1 expression has further been shown to be regulated by promoter methylation. Very recently, however, Kleffel et al. demonstrated that PD-1 expression is not restricted to lymphoid cells but can also be found on malignant melanoma cells. Intrinsic PD-1 expression has been linked to tumor immune evasion and failure to anti-PD-1 treatment. Encouraged by Kleffel et al., we aimed to further complete the insight of the PD-1/PD-L1 pathway’s activity in PCa.","[{'e1': 'high PD-L1 expression ', 'e2': 'adverse outcome', 'relation': 'was significantly associated with ', 'condition': 'In two large independent cohorts'}]"
571,P77P4,"Epigenetic alterations are involved in the regulation of gene expression in key biological processes, i.e. development, differentiation, alternative splicing, and genetic imprinting. In addition, promoter hypermethylation also plays a major role in carcinogenesis altering the expression levels of critical growth regulators. Thereby, gene methylation has turned out to be a potential prognostic biomarker in different tumor entities. Of note, PD-1 DNA methylation had a significant impact on the course of prostate adenocarcinoma in the current study. While PD-1 mRNA expression was highly variable in PCa and did not serve as a prognostic factor in the cohort under investigation, high PD-1 DNA methylation was linked to a BCR 7 months earlier compared to patients with low PD-1 methylation levels. In multivariate Cox proportional hazards analysis, PD-1 DNA methylation furthermore served as a significant prognostic factor in PCa.","[{'e1': 'gene methylation ', 'e2': 'a potential prognostic biomarker ', 'relation': 'has turned out to be ', 'condition': 'in different tumor entities'}, {'e1': 'PD-1 DNA methylation', 'e2': 'prostate adenocarcinoma ', 'relation': ' had a significant impact on the course of ', 'condition': 'in the current study'}, {'e1': 'PD-1 DNA methylation ', 'e2': 'significant prognostic factor ', 'relation': 'served as a ', 'condition': 'in PCa.'}]"
572,P77P5,"In the TCGA cohort, PD-1 DNA methylation was found to be significantly higher in ERG-translocation positive PCa and in tumors with high AR activity scores. This may result from the fact that 5′-fusion partners of ERG, such as TMPRSS2, are highly androgen-responsive as shown by previous studies. AR has a crucial influence on PCa progression, especially in ERG fusion-positive PCa, since AR-activated TMPRSS2, a major fusion partner of ERG, directly regulates the expression of the oncogenic fusion product, thereby controlling cell viability, protein transcription, protein degradation, and cytoskeletal reorganization. In addition, PD-1 promoter methylation and consecutive downregulation of PD-1 protein expression may be influenced by ERG and its oncogenic fusion product in an AR dependent manner. This is in keeping with the observation that PD-L1, PD-1s major receptor ligand, is also significantly associated with AR expression in PCa. Analogously, in breast carcinoma, PD-L1 is more commonly expressed in cancers with lymphocytic infiltrates and AR expression. This implies that sex hormones may significantly influence the subcellular interaction between PD-1 and PD-L1, which may associate with the early observation that estrogen modulates autoimmune responses via the PD-1 receptor. In order to fully characterize the role of PD-1 expression in prostatic adenocarcinoma, however, further mechanistic studies are warranted.","[{'e1': 'PD-1 DNA methylation ', 'e2': ' significantly higher ', 'relation': 'was found to be', 'condition': 'in ERG-translocation positive PCa '}, {'e1': 'PD-1 DNA methylation ', 'e2': ' significantly higher ', 'relation': 'was found to be', 'condition': 'in tumors with high AR activity scores'}, {'e1': 'AR', 'e2': 'PCa progression ', 'relation': ' has a crucial influence on ', 'condition': 'especially in ERG fusion-positive PCa'}, {'e1': 'PD-1 promoter methylation ', 'e2': 'ERG and its oncogenic fusion product ', 'relation': 'may be influenced by ', 'condition': 'in an AR dependent manner'}, {'e1': 'consecutive downregulation of PD-1 protein expression ', 'e2': 'ERG and its oncogenic fusion product ', 'relation': 'may be influenced by ', 'condition': 'in an AR dependent manner'}, {'e1': ' PD-L1, PD-1s major receptor ligand', 'e2': 'AR expression ', 'relation': 'is also significantly associated with ', 'condition': 'in PCa'}, {'e1': 'PD-L1 ', 'e2': 'cancers with lymphocytic infiltrates and AR expression', 'relation': 'is more commonly expressed in ', 'condition': 'in breast carcinoma'}]"
573,P77P6,"In the present study, PD-1 mRNA content in PCa was independent from lymphocytic infiltration and from the stromal amount of the sample, which may potentially be due to a distinctive yet undefined role of PD-1 in PCa glands themselves. Tumor-intrinsic PD-1 expression, however, has only recently been characterized in malignant melanoma cells. This study shows that prostatic adenocarcinoma contains PD-1 mRNA and that PD-1 mRNA is subject to epigenetic PD-1 promoter control in the same way as it has been described for human T-lymphocytes, whose PD-1 expression underlies epigenetic control and is regulated by promoter methylation. This finding may be of significance for the future application of immunotherapies in PCa patients, since intrinsic PD-1 expression has been linked to tumor immune evasion and failure to anti-PD-1 treatment. The experience with PD-1 checkpoint inhibition in PCa is still limited, however, tumor-intrinsic PD-1 DNA methylation interfering with tumor-intrinsic PD-1 functions may have a predictive value for future treatment with checkpoint inhibitors in PCa. The present study bears the strength to combine the analysis of PD-1 promoter methylation in two independent cohorts and by two different molecular assays, indicating that the PD-1 gene is differentially methylated in local and advanced PCa. The University Hospital Bonn cohort revealed a significant association between lower PD-1 methylation and organ confined PCa, which may be due to the altogether higher number of localized tumors compared to the TCGA cohort. In addition, PD-1 methylation correlated with preoperative serum PSA levels in both cohorts. Both parameters are well known to determine the outcome of PCa patients. The latter fact supports the notion that PD-1 promoter methylation qualified as a prognostic biomarker in PCa. However, the prognostic power of PD-1 still needs to be validated in an independent cohort with sufficient follow-up information. Furthermore, the prognostic value should be analyzed with regard to more clinically relevant endpoints, i.e. PCa-specific survival which was unfortunately not available for the analyzed cohorts. In addition, the retrospective nature of the present study further adds to its major limitations.","[{'e1': ' PD-1 methylation ', 'e2': 'preoperative serum PSA levels ', 'relation': 'correlated with ', 'condition': 'in both cohorts'}]"
574,P77P9,"The present study reveals that PD-1 promoter methylation strongly modulates the expression of the immune checkpoint regulator PD-1 in PCa in that it inversely correlates with PD-1 mRNA expression. In addition, the significant positive correlation of PD-1 methylation and negative correlation of PD-1 mRNA with AR might indicate an intrinsic role of PD-1 in PCa carcinogenesis and progression. In this study, PD-1 promoter methylation serves as a significant predictor of BCR-free survival in PCa patients and adds significant independent prognostic information adjunct to pT-stage and Gleason grade. Hence, PD-1 methylation might help to personalize individual therapies. Furthermore, the presented data suggest a yet unknown role in PCa cells, which might be exploited to develop new therapy strategies for PCa in the future.","[{'e1': ' PD-1 promoter methylation ', 'e2': 'the expression of the immune checkpoint regulator PD-1 ', 'relation': 'strongly modulates ', 'condition': 'in PCa'}, {'e1': 'the significant positive correlation of PD-1 methylation', 'e2': ' intrinsic role of PD-1', 'relation': 'with AR might indicate an', 'condition': ' in PCa carcinogenesis and progression'}, {'e1': ' negative correlation of PD-1 mRNA', 'e2': ' intrinsic role of PD-1', 'relation': 'with AR might indicate an', 'condition': ' in PCa carcinogenesis and progression'}, {'e1': 'PD-1 promoter methylation ', 'e2': 'significant predictor of BCR-free survival ', 'relation': 'serves as a ', 'condition': 'in PCa patients'}]"
575,P78P1,"Deletion of 18q recurrently occurs in prostate cancer. To evaluate its clinical relevance, dual labeling fluorescence in-situ hybridization using probes for 18q21 and centromere 18 was performed on a prostate cancer tissue microarray. An 18q deletion was found in 517 of 6,881 successfully analyzed cancers. 18q deletion was linked to unfavorable tumor phenotype. An 18q deletion was seen in 6.4% of 4,360 pT2, 8.0% of 1,559 pT3a and 11.8% of 930 pT3b-pT4 cancers. Deletions of 18q were detected in 6.9% of 1,636 Gleason ≤ 3 + 3, 6.8% of 3,804 Gleason 3 + 4, 10.1% of 1,058 Gleason 4 + 3, and 9.9% of 344 Gleason ≥ 4 + 4 tumors. Deletions of 18q were slightly more frequent in ERG-fusion negative than in ERG-fusion positive cancers. 18q deletions were also linked to biochemical recurrence. This was independent from established pre- and postoperative prognostic factors. In summary, the results of our study identify 18q deletion as an independent prognostic parameter in prostate cancer. As it is easy to measure, 18q deletion may be a suitable component for multiparametric molecular prostate cancer prognosis tests.","[{'e1': '18q deletion ', 'e2': 'independent prognostic parameter', 'relation': 'identified as an ', 'condition': ' in prostate cancer'}]"
576,P78P2,"Prostate cancer is one of the most frequent cancer types in males worldwide. About one million patients are diagnosed with this disease every year, and almost 140,000 eventually die from their cancer in Western societies. Autopsy studies suggest that up to 70% of males will develop prostate cancer during their lifetime, but clinical experience shows that only a minority of patients will develop life-threatening disease that requires radical treatment. As screening strategies identify prostate cancers already at early stages of the disease, it becomes increasingly important to avoid overtreatment of patients with less aggressive disease. Accordingly, it will be important to establish molecular markers enabling an early distinction between the indolent and aggressive forms of the disease.","[{'e1': 'almost 140,000 ', 'e2': 'cancer ', 'relation': 'eventually die from their ', 'condition': 'in Western societies'}]"
577,P78P7,"Deletions of 18q were significantly associated with advanced tumor stage, high Gleason grade and increased risk of biochemical recurrence. These findings are in line with earlier studies on 23–46 prostate cancers reporting higher frequencies of loss of heterozygosity at 18q21 in tumors with advanced stage, high Gleason grade and metastatic growth. That the prognostic impact of 18q deletions was independent of established prognostic features, both in preoperative and in postoperative scenarios, highlights the potential clinical applicability of 18q deletion measurement. The Gleason grade is the strongest known prognostic parameter in prostate cancer. A comparison with established prognostic Gleason grade groups revealed that 18q deletion was even able to distinguish prognostic subgroups within Gleason 3 + 3 and 3 + 4 cancers. This is of particular interest because these are the low and intermediate risk tumors where the clinical decision making is most difficult and where the therapeutic options often range from active surveillance to radical prostatectomy.","[{'e1': 'the prognostic impact of 18q deletions', 'e2': ' established prognostic features', 'relation': ' was independent of', 'condition': 'in preoperative '}, {'e1': 'the prognostic impact of 18q deletions', 'e2': ' established prognostic features', 'relation': ' was independent of', 'condition': 'in postoperative scenarios'}]"
578,P78P8,"Based on the morphologic analysis of more than 10,000 prostate cancers, we had recently shown that prognostic Gleason grade information can be expanded by using the percentage of unfavorable Gleason patterns as a continuous variable. Both in biopsies and in prostatectomy samples, prostate cancer prognosis continuously deteriorates with increasing percentage of unfavorable Gleason pattern found in a cancer. The lack of an unequivocal prognostic impact of 18q deletion in most subgroups defined by a comparable quantitative Gleason grade illustrates how difficult it is for a molecular parameter to outperform established morphological parameters of malignancy. However, a variety of molecular features have recently been identified. We thus anticipate that a clinically useful molecular prostate cancer prognosis test combining a number of strong prognostic biomarkers will become feasible. Because of the simple and reproducible analysis of 18q deletions always resulting in a yes/no answer, we believe that 18q deletions could be a suitable element for such a test.","[{'e1': ' prostate cancer prognosis ', 'e2': ' increasing percentage of unfavorable Gleason pattern found in a cancer', 'relation': 'continuously deteriorates with', 'condition': 'in biopsies'}, {'e1': ' prostate cancer prognosis ', 'e2': ' increasing percentage of unfavorable Gleason pattern found in a cancer', 'relation': 'continuously deteriorates with', 'condition': 'in prostatectomy samples'}]"
579,P79P10,"Our data suggest PTEN inactivation as a possible candidate for a molecular aberration that could particularly efficiently interplay with 8p deletion. PTEN deletion is the strongest single molecular prognostic feature in prostate cancer known as yet. The strong statistical association between PTEN and 8p deletions and the particularly poor clinical course in case of a co-deletion of PTEN and 8p argues for synergistic effects between these lesions. The 8p genes possibly involved in such an interaction remain unclear. However, mouse models suggest that PTEN loss could drive invasion and metastasis in cooperation with loss of NKX3.1. Earlier studies had demonstrated that the panel of chromosomal deletions occurring in prostate cancer is largely dependent on the ERG status. Deletions of PTEN, 16q, and 3p13 are tightly linked to ERG expression while deletions of 6q15 and 5q21 are largely restricted to ERG-negative cancers. The data of the present study delineate 8p deletion as the exceptional case of an “ERG-independent” deletion. This is also supported by CGH array data from a cohort of 181 prostate cancers, where no significant link between 8p deletion and ERG fusion was reported. Our data demonstrate that the slightly higher rate of 8p deletions in ERG-positive than in ERG-negative cancers is entirely driven by its strong association with the ERG-linked PTEN deletion.","[{'e1': 'PTEN loss ', 'e2': 'invasion and metastasis ', 'relation': 'could drive ', 'condition': 'in cooperation with loss of NKX3.1'}, {'e1': ' panel of chromosomal deletions ', 'e2': 'the ERG status', 'relation': ' is largely dependent on ', 'condition': 'in prostate cancer'}, {'e1': ' slightly higher rate of 8p deletions', 'e2': 'its strong association with the ERG-linked PTEN deletion.', 'relation': ' is entirely driven by ', 'condition': 'in ERG-positive than in ERG-negative cancers '}]"
580,P79P3,"Deletions of chromosome 8p are of high interest in prostate cancer. After TMPRSS2:ERG fusion, 8p deletions constitute the second most frequent genomic alteration in this tumor type, occurring in about 30% of cancers. A specific target gene of the 8p deletion has never been identified. It appears likely that the tumorigenic effect of 8p deletions occurs through a combined downregulation of multiple relevant genes on 8p. A variety of studies have earlier analyzed 8p deletions in prostate cancer and reported associations with advanced tumor stage and Gleason grade, metastatic growth, early biochemical recurrence, and reduced overall survival. Most of these studies were done on patient cohorts ranging from 27 to 195. In an own study on 2,097 cancers we had only found a marginal association with clinical outcome.","[{'e1': 'Deletions of chromosome 8p ', 'e2': 'high interest ', 'relation': 'are of ', 'condition': 'in prostate cancer'}, {'e1': '8p deletions ', 'e2': 'second most frequent genomic alteration ', 'relation': 'constitute the ', 'condition': 'in this tumor type, occurring in about 30% of cancers'}]"
581,P79P5,"Chromosome 8p deletion is one of the most frequent alterations in many different cancer types. 8p deletions are typically large and often involve the entire short arm of the chromosome. This made the search for 8p deletion target genes difficult. Extensive studies searching for the underlying tumor suppressor gene have failed to identify a universal 8p tumor suppressor but have revealed multiple 8p genes with documented tumor suppressive properties, such as NKX3.1, CSMD1, DLC1, PPP2CB and PPP3CC, MSR1, TNFRSF10C and TNFRSF10D. Studies employing whole genome or exome sequencing have meanwhile clarified that 8p deletion is, in the vast majority of cases, not accompanied by a mutation of the coding area of any 8p gene. It is still possible that one or several 8p-deleted genes are completely silenced by epigenetic or other mechanisms. It is an appealing alternative, however, that reduced expression of a combination of 8p genes could exert biologically relevant consequences in case of heterozygous 8p deletion. Studies in murine models of hepatocellular carcinomas, another cancer type frequently affected by large 8p deletions, have shown that partial inactivation of several 8p genes can cooperatively drive cancer development, thus supporting a model of compound haplo-insufficiency which might also apply for 8p-deleted prostate cancers. A significant biologic impact of haplo-insufficiency has recently also been demonstrated for NKX3.1.","[{'e1': 'Chromosome 8p deletion ', 'e2': 'most frequent alterations ', 'relation': 'is one of the ', 'condition': 'in many different cancer types'}]"
582,P79P8,"The variable prognostic impact of 8p deletions in cancers with different Gleason grades is of particular interest. That 8p deletions were prognostically most relevant in the subgroup of 3 + 4 carcinomas in univariate as well as in multivariate analysis, when combined with Gleason score, is encouraging because Gleason 3 + 4 represents the clinically most difficult group with treatment options ranging from active surveillance to prostatectomy. These data also illustrate that the subgroup Gleason 3 + 4 is more heterogeneous than others in clinical outcome. Based on the morphologic analysis of more than 10,000 prostate cancers, we had recently shown that prognostic Gleason grade information can be expanded in Gleason 3 + 4 and 4 + 3 cancers by using the percentage of Gleason 4 patterns as a continuous variable. Both in biopsies and in prostatectomy samples, prostate cancer prognosis continuously deteriorated with increasing percentage of Gleason 4 pattern. That a statistically significant prognostic impact of 8p deletion only remained in few subgroups defined by a comparable quantitative Gleason grade illustrates how difficult it is for a molecular parameter to outperform morphological parameters of malignancy in prostate cancer.","[{'e1': 'prognostic Gleason grade information ', 'e2': 'using the percentage of Gleason 4 patterns as a continuous variable', 'relation': 'can be expanded by ', 'condition': 'in Gleason 3 + 4 and 4 + 3 cancers'}, {'e1': ' prostate cancer prognosis ', 'e2': 'increasing percentage of Gleason 4 pattern', 'relation': 'continuously deteriorated with ', 'condition': 'in biopsies '}, {'e1': ' prostate cancer prognosis ', 'e2': 'increasing percentage of Gleason 4 pattern', 'relation': 'continuously deteriorated with ', 'condition': 'in prostatectomy samples'}]"
583,P80P1,"Prostate cancer is the most commonly diagnosed cancer among men in the United States as well as most Western countries. A significant proportion of men report having a positive family history of prostate cancer in a first-degree relative (father, brother, son), which is important in that family history is one of the only established risk factors for the disease and plays a role in decision-making for prostate cancer screening. Familial aggregation of prostate cancer is considered a surrogate marker of genetic susceptibility to developing the disease, but shared environment cannot be excluded as an explanation for clustering of cases among family members. Prostate cancer is both a clinically and genetically heterogeneous disease with inherited factors predicted to account for 40%–50% of cases, comprised of both rare highly to moderately penetrant gene variants, as well as common genetic variants of low penetrance. Most notably, HOXB13 and BRCA2 mutations have been consistently shown to increase prostate cancer risk, and are more commonly observed among patients diagnosed with early-onset disease. A recurrent mutation in HOXB13 has been shown to predispose to hereditary prostate cancer (HPC), and BRCA2 mutations to hereditary breast and ovarian cancer (HBOC). Genome-wide association studies (GWAS) have also identified approximately 100 loci that associate with modest (odds ratios < 2.0) increases in prostate cancer risk, only some of which have been replicated in subsequent studies. Despite these efforts, genetic testing in prostate cancer lags behind other common tumors like breast and colorectal cancer. To date, National Comprehensive Cancer Network (NCCN) guidelines have highly selective criteria for BRCA1/2 testing for men with prostate cancer based on personal history and/or specific family cancer history. Tumor sequencing is also leading to the identification of germline mutations in prostate cancer patients, informing the scope of inheritance. Advances in genetic testing for inherited and familial prostate cancer (FPC) are needed to inform personalized cancer risk screening and treatment approaches.","[{'e1': '100 loci ', 'e2': 'modest (odds ratios < 2.0) increases', 'relation': 'that associate with ', 'condition': ' in prostate cancer risk'}, {'e1': 'Tumor sequencing ', 'e2': 'the identification of germline mutations ', 'relation': 'is also leading to ', 'condition': 'in prostate cancer patients'}]"
584,P81P1,"Radioresistance remains a significant obstacle in the treatment of Prostate Cancer (PCa). To simulate the clinical scenario of irradiation resistance (IRR), we created DU145-IRR PCa cell lines by treatment with 2 Gy daily IR for 59 fractions. DU145-IRR cells acquired an aggressive phenotype as evidenced by increased clonogenic survival, tumorigenic potential and invasiveness. We performed transcriptome profiling to discover dysregulated genes in DU145-IRR cells and identified the long non-coding RNA (lncRNA), Urothelial carcinoma-associated 1 (UCA1). We first investigated the role of UCA1 in radiation response and found that UCA1 abundance was significantly higher in DU145-IRR cells compared to control cells. UCA1 siRNA-knockdown reversed the aggressive phenotype and significantly increased sensitivity to IR. UCA1 depletion inhibited growth, induced cell cycle arrest at the G2/M transition and decreased activation of the pro-survival Akt pathway. We then studied the clinical significance of UCA1 expression in two independent cohorts of PCa patients: MSKCC (130 patients) and CPC-GENE (209 patients). UCA1 over-expression was associated with decreased 5-year disease-free survival in MSKCC patients and a trend toward lower biochemical recurrence-free survival in CPC-GENE patients. We showed for the first time that UCA1 depletion induces radiosensitivity, decreases proliferative capacity and disrupts cell cycle progression, which may occur through altered Akt signaling and induced cell cycle arrest at the G2/M transition. Our results indicate that UCA1 might have prognostic value in PCa and be a potential therapeutic target.","[{'e1': 'transcriptome profiling ', 'e2': 'dysregulated genes ', 'relation': 'to discover ', 'condition': 'in DU145-IRR cells'}, {'e1': 'UCA1 abundance ', 'e2': ' in DU145-IRR cells ', 'relation': 'was significantly higher', 'condition': 'compared to control cells'}, {'e1': 'UCA1 over-expression ', 'e2': 'decreased 5-year disease-free survival ', 'relation': 'was associated with ', 'condition': 'in MSKCC patients'}, {'e1': 'UCA1 over-expression ', 'e2': 'a trend towards lower biochemical recurrence-free survival ', 'relation': 'was associated with ', 'condition': 'in CPC-GENE patients'}]"
585,P81P10,"The effect of UCA1 on radiation response appears to be partly related to its role in cell cycle regulation. In bladder carcinoma cells, UCA1 regulates cell cycle progression through CREB and via PI3K-AKT-dependent signalling pathways. Our findings similarly suggest that UCA1 can modulate radiosensitivity of PCa cells by impairing cell cycle progression, potentially through downregulation of the PI3K/Akt pathway. Future experiments employing RNAseq to capture the transcriptomic landscape regulated by UCA1 may contribute to additional mechanistic findings.","[{'e1': 'The effect of UCA1 on radiation response ', 'e2': 'its role ', 'relation': 'appears to be partly related to ', 'condition': 'in cell cycle regulation'}, {'e1': ' UCA1', 'e2': 'cell cycle progression ', 'relation': ' regulates ', 'condition': 'through CREB '}, {'e1': ' UCA1', 'e2': 'cell cycle progression ', 'relation': ' regulates ', 'condition': 'via PI3K-AKT-dependent signalling pathways'}, {'e1': 'UCA1', 'e2': 'radiosensitivity of PCa cells ', 'relation': ' can modulate ', 'condition': 'by impairing cell cycle progression, potentially through downregulation of the PI3K/Akt pathway'}]"
586,P81P11,"UCA1 knockdown reversed the aggressive phenotype in DU145 and PC3 PCa cells. The findings that UCA1 knockdown decreased proliferation and tumorigenesis without affecting cellular invasion are consistent with previous studies indicating that proliferation and invasion are two distinct processes under the control of different signaling pathways. For example, it has been demonstrated in glioma that invasion, migration and branching morphogenesis are exclusive characteristics of highly invasive cells while highly proliferative cells are highly tumorigenic and display anchorage-independent growth in soft agar.","[{'e1': 'UCA1 knockdown ', 'e2': 'aggressive phenotype ', 'relation': 'reversed the ', 'condition': 'in DU145 cells.'}, {'e1': 'UCA1 knockdown ', 'e2': 'aggressive phenotype ', 'relation': 'reversed the ', 'condition': 'in PC3 PCa cells.'}, {'e1': 'UCA1 knockdown ', 'e2': 'proliferation', 'relation': 'decreased ', 'condition': 'without affecting cellular invasion'}, {'e1': 'UCA1 knockdown ', 'e2': ' tumorigenesis ', 'relation': 'decreased ', 'condition': 'without affecting cellular invasion'}, {'e1': 'proliferative cells ', 'e2': 'anchorage-independent growth ', 'relation': 'are highly tumorigenic and display ', 'condition': 'in soft agar.'}]"
587,P81P12,"LncRNAs can be used as diagnostic and prognostic biomarkers for PCa. We showed that UCA1 over-expression was associated with an unfavorable outcome in two separate cohorts of PCa patients including a large number of patients with long follow-up data. These observations were in agreement with a recent study on a small cohort of 40 patients treated with surgery reporting that patients with high UCA1 levels had poorer prognosis. These findings support further investigations into UCA1 as a prognostic biomarker in other PCa patient cohorts. UCA1 has been shown to serve as a potential diagnostic biomarker for bladder, lung and gastric malignancies. In our laboratory, we have found that UCA1 expression can be detected and quantitated from PCa patient post-digital rectal examination urine samples using qRT-PCR and higher UCA1 expression is associated with higher Gleason score. The potential of lncRNAs as diagnostic biomarker approach is beautifully demonstrated by the PCA3 test, which is a validated test based upon the detection of the lncRNA PCA3. We believe that UCA1 may represent a potential biomarker for PCa diagnosis.","[{'e1': 'UCA1 over-expression ', 'e2': ' an unfavorable outcome ', 'relation': 'was associated with', 'condition': 'in two separate cohorts of PCa patients including a large number of patients with long follow-up data'}]"
588,P81P13,"In conclusion, UCA1 may regulate PCa cell proliferation, tumorigenesis, cell cycle progression and radiosensitivity through its effects on different target genes. These target genes could differ among specific tissues and cell types. Although the precise role of UCA1 in PCa development remains unclear; the results from the present study support UCA1 as a novel lncRNA that influences radiation response, and represents a potential biomarker for PCa diagnosis and help guide therapy decisions for patients in the future.","[{'e1': 'UCA1 ', 'e2': 'PCa cell proliferation', 'relation': 'may regulate ', 'condition': 'through its effects on different target genes'}, {'e1': 'UCA1 ', 'e2': 'tumorigenesis ', 'relation': 'may regulate ', 'condition': 'through its effects on different target genes'}, {'e1': 'UCA1 ', 'e2': 'cell cycle progression ', 'relation': 'may regulate ', 'condition': 'through its effects on different target genes'}, {'e1': 'UCA1 ', 'e2': 'radiosensitivity ', 'relation': 'may regulate ', 'condition': 'through its effects on different target genes'}]"
589,P81P3,"Long non-coding RNAs (lncRNAs) are a group of non-coding transcripts of more than 200 nucleotides that function in a broad range of cellular processes, such as cell growth, survival, migration, invasion, and differentiation. They are also involved in tumorigenesis and metastasis as well as radiotherapy and chemotherapy resistance. LncRNAs are highly deregulated in tumors and have been found to act as tumor suppressors or oncogenes. Recent studies indicate that lncRNAs play important biological and clinical roles in PCa; and overexpression of oncogenic lncRNAs may promote tumor cell proliferation and metastasis.","[{'e1': 'lncRNAs ', 'e2': 'important biological and clinical roles ', 'relation': 'play ', 'condition': 'in PCa'}]"
590,P81P4,"Urothelial carcinoma associated 1 (UCA1) is a recently identified lncRNA with aberrant expression in various types of cancer. UCA1 expression regulates cancer cell proliferation, migration, and invasion. Recent studies have shown that UCA1 is a functional oncogenic lncRNA upregulated in several malignancies. UCA1 abundance is correlated with clinico-pathological parameters, particularly in bladder cancer, suggesting higher abundance as a marker of higher histologic grade.","[{'e1': 'UCA1 abundance ', 'e2': 'clinico-pathological parameters', 'relation': 'is correlated with ', 'condition': 'particularly in bladder cancer'}]"
591,P81P5,"The biological role and clinical significance of UCA1 in PCa carcinogenesis and therapy response are not yet well understood. Here, for the first time, we show that irradiation-resistant (IRR) PCa cells express a significantly higher level of UCA1 in vitro and UCA1-knockdown reverses the aggressive phenotype and improves radiosensitivity. Our data suggest that UCA1 contributes to radiotherapy resistance through regulation of the PI3K/Akt pathway. The biological role of UCA1 in tumor proliferation, invasion, tumorigenesis, cell cycle progression and DNA repair were investigated. We showed that the higher expression of UCA1 is associated with unfavorable outcome in two separate cohorts of PCa patients.","[{'e1': 'UCA1 ', 'e2': 'radiotherapy resistance ', 'relation': 'contributes to ', 'condition': 'through regulation of the PI3K/Akt pathway'}, {'e1': 'the higher expression of UCA1', 'e2': 'unfavorable outcome ', 'relation': ' is associated with ', 'condition': 'in two separate cohorts of PCa patients.'}]"
592,P81P6,"Radioresistance remains a significant obstacle in the treatment of many cancers including PCa, limiting treatment success and negatively affecting patient outcomes. LncRNAs are regulators of normal biological processes, neoplastic development and progression, and radiotherapy/chemotherapy resistance. The expression levels of lncRNAs have been associated with carcinogenesis and tumor growth in PCa.","[{'e1': 'Radioresistance ', 'e2': 'significant obstacle ', 'relation': 'remains a ', 'condition': 'in the treatment of many cancers including PCa'}, {'e1': 'The expression levels of lncRNAs ', 'e2': 'carcinogenesis and tumor growth ', 'relation': 'have been associated with ', 'condition': 'in PCa.'}]"
593,P81P7,"UCA1 was originally identified as being overexpressed in bladder cancer and it functions as an oncogenic lncRNA in a variety of different tumor types. We found that UCA1 expression was strikingly high in PCa cells resistant to IR, suggesting its role in therapy resistance. The effect of UCA1 expression in tumor progression, invasion and metastasis is previously described. However, the biological role and underlying mechanism of UCA1 in RT response has remained undefined. We discovered UCA1 as one of the important mediators of radiation response. Using a siRNA knockdown strategy, we further demonstrated that UCA1 knockdown could improve radiosensitivity in both classic PCa cell lines and IRR-PCa cells, and largely reverse the aggressive phenotype observed. To our knowledge, this is the first study investigating the impact of UCA1 on response to radiation in cancer cells.","[{'e1': 'UCA1 ', 'e2': 'overexpressed ', 'relation': 'was originally identified as being ', 'condition': 'in bladder cancer '}, {'e1': 'UCA1 ', 'e2': 'an oncogenic lncRNA', 'relation': 'functions as ', 'condition': ' in a variety of different tumor types'}, {'e1': 'UCA1 knockdown ', 'e2': ' radiosensitivity ', 'relation': 'could improve', 'condition': 'in classic PCa cell lines '}, {'e1': 'UCA1 knockdown ', 'e2': ' radiosensitivity ', 'relation': 'could improve', 'condition': 'in IRR-PCa cells'}, {'e1': 'the impact of UCA1 ', 'e2': 'radiation ', 'relation': 'on response to ', 'condition': 'in cancer cells.'}]"
594,P81P8,"Molecular mechanisms contributing to therapy resistance in PCa are complex. Recent evidence suggest that PI3K/Akt/phosphatase and tensin homolog (PTEN)/mammalian target of rapamycin (mTOR) signaling pathway, autophagy, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) play important roles in PCa tumorigenesis and may collectively contribute to radioresistance. Activation of the PI3K/Akt pathway confers cancer resistance to radiation, and inhibition of this pathway can re-sensitize PCa cells to IR. Previous data indicates that the PI3K/Akt/mTOR pathway is the most activated pathway associated with radioresistance in three PCa-IRR cell lines developed by irradiating these with 2Gy per day for only five consecutive days. We believe that our DU145-IRR cells, which have survived a significantly higher total dose of RT delivered over several weeks, are representative of a radioresistant phenotype that best mimics the clinical scenario.","[{'e1': 'PI3K/Akt/mTOR pathway', 'e2': 'radioresistance', 'relation': 'is the most activated pathway associated with', 'condition': 'in three PCa-IRR cell lines developed by irradiation with 2 Gy per day for five consecutive days'}]"
595,P81P9,Our results suggest that UCA1 knockdown reduces Akt activation and consequently improves sensitivity to radiation. The process of radiation resistance involves many molecular pathways. The expression and dysregulation of lncRNAs are highly cancer type specific. UCA1 may regulate therapy response in PCa tumors through its effects on different target genes. The selection of targets may also vary depending on physiological contexts or distinct tumor microenvironment.,"[{'e1': ' UCA1 ', 'e2': 'therapy response through its effects on different target genes', 'relation': 'may regulate ', 'condition': 'in PCa tumors'}]"
596,P82P10,"In this case-control study, we investigated the SNPs associated with familial clusters and the prognosis of patients with PC. Considering the development of PC, we found that the polymorphic allele and genotype of the SNP rs2660753 were significantly more prevalent in controls, which suggests that these polymorphisms may play a protective role against the development of PC in our population. The SNP rs2660753 is a PC susceptibility polymorphism that was identified in a genome-wide association study in Europeans and has been validated for different populations of Europeans and non-Europeans. The nearest genes to the region rs2660753 are VGLL3, CHMP2B and Pit-1/POU1F1, which encode proteins with potential roles in tumorigenesis. VGLL3 encodes a colon carcinoma-related protein. POU1F1 encodes POU domain class 1 transcription factor 1. POU1F1 is a pituitary-specific transcription factor that is centrally involved in regulating growth hormone synthesis. It is expressed in normal and human breast tumors and regulates GH secretion and cell proliferation. CHMP2B encodes chromatin-modifying protein 2B. CHMP2B belongs to the chromatin-modifying protein/charged multivesicular body protein family. In addition, the 3p12.3-pcen region has been identified as a locus harboring candidate to a tumor suppressor gene. However, the same SNP rs2660753 on chromosome 3 was not correlated with PC in Chinese patients.","[{'e1': 'these polymorphisms ', 'e2': 'a protective role against the development of PC ', 'relation': 'may play ', 'condition': 'in our population'}, {'e1': ' VGLL3, CHMP2B and Pit-1/POU1F1', 'e2': 'proteins with potential roles ', 'relation': 'encode ', 'condition': 'in tumorigenesis'}, {'e1': 'the same SNP rs2660753 on chromosome 3 ', 'e2': 'PC ', 'relation': 'was not correlated with ', 'condition': 'in Chinese patients.'}]"
597,P82P2,"Considering susceptibility, the polymorphic allele in the SNP rs2660753 on chromosome 3 was significantly more prevalent in controls. For familial clustering, the polymorphic homozygote genotype of the SNP rs7931342 was five times more frequent in patients with familial PC compared to sporadic PC. Regarding the SNP 1447295, the polymorphic homozygote genotype was more prevalent in patients with organ-confined PC, and most importantly, the polymorphic allele occurred more frequently in patients without biochemical recurrence. Kaplan-Meier analysis showed a median biochemical recurrence free survival of 124.2 compared to 85.6 months for patients with the wild-type allele.","[{'e1': 'the polymorphic allele ', 'e2': 'SNP rs2660753 on chromosome 3 was significantly more prevalent', 'relation': 'in the ', 'condition': ' in controls'}, {'e1': 'the polymorphic homozygote genotype ', 'e2': 'SNP rs7931342 was five times more frequent ', 'relation': 'of the ', 'condition': 'in patients with familial PC compared to sporadic PC'}]"
598,P83P1,"It is widely appreciated that reactive stroma or carcinoma-associated fibroblasts can influence epithelial tumor progression. In prostate cancer (PCa), the second most common male malignancy worldwide, the amount of reactive stroma is variable and has predictive value for tumor recurrence. By analyzing human PCa protein and RNA expression databases, we found smooth muscle cells (SMCs) are decreased in advanced tumors, whereas fibroblasts are maintained. In three mouse models of PCa, PB-MYC, ERG/PTEN and TRAMP, we found the composition of the stroma is distinct. SMCs are greatly depleted in advanced PB-MYC tumors and locally reduced in ERG/PTEN prostates, whereas in TRAMP tumors the SMC layers are increased. In addition, interductal fibroblast-like cells expand in PB-MYC and ERG/PTEN tumors, whereas in TRAMP PCa they expand little and stromal cells invade into intraductal adenomas. Fate mapping of SMCs showed that in PB-MYC tumors the cells are depleted, whereas they expand in TRAMP tumors and interestingly contribute to the stromal cells in intraductal adenomas. Hedgehog (HH) ligands secreted by epithelial cells are known to regulate prostate mesenchyme expansion differentially during development and regeneration. Any possible role of HH signaling in stromal cells during PCa progression is poorly understood. We found that HH signaling is high in SMCs and fibroblasts near tumor cells in all models, and epithelial Shh expression is decreased whereas Ihh and Dhh are increased. In human primary PCa, expression of IHH is the highest of the three HH genes, and elevated HH signaling correlates with high stromal gene expression. Moreover, increasing HH signaling in the stroma of PB-MYC PCa resulted in more intact SMC layers and decreased tumor progression (micro-invasive carcinoma). Thus, we propose HH signaling restrains tumor progression by maintaining the smooth muscle and preventing invasion by tumor cells. Our studies highlight the importance of understanding how HH signaling and stromal composition impact on PCa to optimize drug treatments.","[{'e1': 'the cells expand in TRAMP tumors ', 'e2': 'the stromal cells ', 'relation': 'and interestingly contribute to ', 'condition': 'in intraductal adenomas'}, {'e1': 'the amount of reactive stroma is variable ', 'e2': 'tumor recurrence.', 'relation': 'and has predictive value for ', 'condition': ' In prostate cancer (PCa)'}, {'e1': 'elevated HH signaling', 'e2': 'high stromal gene expression', 'relation': ' correlates with ', 'condition': ' In human primary PCa'}]"
599,P83P10,"A majority of the studies on the role of HH signaling using PCa cell lines have suggested that HH pathway blockade via cyclopamine treatment suppresses tumor growth. Using an in vivo genetic mouse model that reflects the changes in stromal content of human PCa, however, we found that aberrant activation of HH signaling in the Gli1-expressing subset of stromal cells in PB-MYC tumors results in decreased tumor progression, revealing that tumor stroma can restrain PCa progression. We propose that the partially restored smooth muscle layers act as a barrier to prevent epithelial cells from invading into the stroma. It is also possible that SMCs secrete factors, such as pro-differentiation proteins, that restrain tumor progression. Together with several recent studies showing that inhibition of HH signaling in the stroma of pancreas and bladder cancers decreases survival, our findings offer an explanation for the unsuccessful clinical trials using small-molecule HH antagonists for PCa. Further research into genetic models that represent later stages of human PCa will provide additional evidence for the value of altering HH function for PCa patients.","[{'e1': 'HH pathway blockade treatment ', 'e2': 'tumor growth', 'relation': 'suppresses ', 'condition': 'via cyclopamine'}, {'e1': 'inhibition of HH signaling ', 'e2': 'survival', 'relation': 'decreases ', 'condition': 'in the stroma of pancreas and bladder cancers'}]"
600,P83P2,"Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men in the United States and the second most common malignancy in men worldwide. Although prostate carcinoma arises from the epithelium, numerous studies have revealed the potential influence of reciprocal interactions between prostate stromal cells (fibroblasts and smooth muscle cells or SMCs) and cancer epithelial cells on tumor progression. For example, human prostate carcinoma-associated fibroblasts, but not normal prostate fibroblasts, induce substantial growth and neoplasia of nonmalignant human prostate epithelial cell lines in tissue recombinants in mice. Furthermore, the proportion of reactive stroma within human PCa samples has prognostic value for PCa-specific death. Unlike normal prostate stroma that is primarily composed of mature SMCs, the reactive stroma of human PCa has been described as enriched with myofibroblasts and fibroblasts, and depleted of mature SMCs. In the normal adult mouse prostate, our recent study identified four stromal subtypes: SMCs that express smooth muscle actin, fibroblasts scattered between prostate ducts, and two additional vimentin-expressing ductal fibroblast-like cell types – “wrapping cells” that wrap the outside of the smooth muscle layer and “subepithelial cells” situated between the smooth muscle and the epithelium. Furthermore, genetic inducible fate mapping studies during regeneration of the adult prostate raised the possibility that each stromal subtype has a distinct stem or progenitor cell. The relationship between the different stromal lineages and cancer reactive stromal cells are not known, nor whether a particular subtype is tumor protective.","[{'e1': 'human prostate carcinoma-associated fibroblasts ', 'e2': 'substantial growth and neoplasia of nonmalignant human prostate epithelial cell lines ', 'relation': 'induce ', 'condition': 'in tissue recombinants in mice'}, {'e1': ' SMCs ', 'e2': 'smooth muscle actin', 'relation': 'that express ', 'condition': ' In the normal adult mouse prostate'}, {'e1': 'fibroblasts ', 'e2': 'prostate ducts', 'relation': 'scattered between ', 'condition': ' In the normal adult mouse prostate'}, {'e1': ' two additional vimentin-expressing ductal fibroblast-like cell types – “wrapping cells” ', 'e2': 'the smooth muscle layer and “subepithelial cells” situated between the smooth muscle and the epithelium', 'relation': 'that wrap the outside of ', 'condition': ' In the normal adult mouse prostate'}]"
601,P83P3,"The hedgehog (HH) signaling pathway plays a pivotal role in development and regeneration of the adult prostate, and abnormal HH signaling has been implicated in multiple carcinomas including PCa. In mammals, three HH ligands, sonic (SHH), indian (IHH), and desert (DHH), exert their function by binding to the receptor patched, which relieves inhibition of the transmembrane protein smoothened. SMO activation leads to the formation of GLI2 and GLI3 transcriptional activators, which induce target genes including Gli1 and Ptch1. Because Gli1 expression is dependent on GLI2 and GLI3 activators, it is a sensitive readout of high-level HH signaling. The HH signaling pathway has stage-specific roles during prostate development. During embryonic development HH signaling acts on the mesenchyme to promote ductal extension and branching, whereas at the early postnatal stage HH plays an inhibitory role on ductal morphogenesis. In the adult mouse prostate, our previous study showed that SHH is secreted by basal epithelial cells and signals to progenitors of all four stromal subtypes. A separate study using an IhhCreER knock-in allele revealed that during adult prostate regeneration Ihh is preferentially expressed by epithelial cells between growing buds, and functional studies indicate that IHH negatively regulates epithelial bud formation by downregulating stromal Hgf. However, it has not been addressed experimentally whether any specific function of HH signaling is involved in the stromal changes seen during PCa progression.","[{'e1': 'The hedgehog (HH) signaling pathway ', 'e2': 'pivotal role ', 'relation': 'plays a ', 'condition': 'in development '}, {'e1': 'The HH signaling pathway ', 'e2': 'stage-specific roles ', 'relation': 'has ', 'condition': 'during prostate development'}, {'e1': ' HH signaling ', 'e2': 'the mesenchyme to promote ductal extension and branching', 'relation': 'acts on ', 'condition': ' During embryonic development'}, {'e1': 'HH ', 'e2': 'inhibitory role ', 'relation': 'plays an ', 'condition': 'on ductal morphogenesis'}, {'e1': ' SHH ', 'e2': 'basal epithelial cells ', 'relation': 'is secreted by ', 'condition': ' In the adult mouse prostate'}, {'e1': ' SHH ', 'e2': 'progenitors of all four stromal subtypes', 'relation': 'signals to ', 'condition': ' In the adult mouse prostate'}, {'e1': ' Ihh ', 'e2': 'epithelial cells between growing buds', 'relation': 'is preferentially expressed by ', 'condition': 'during adult prostate regeneration'}]"
602,P83P4,"Several studies have provided evidence for paracrine HH signaling in human and mouse PCa, a cellular relationship resembling the epithelial-to-stromal HH signaling in developing and adult mouse prostates. Autocrine HH signaling in PCa epithelial cells has also been reported, particularly in advanced and metastatic PCa specimens. Given the questionable reliability of antibodies to HH pathway components, the highly heterogeneous nature of PCa, and the difficulty of effectively separating tumor cells from the stroma, we have taken advantage of mouse genetic tools to study HH signaling in vivo during PCa progression in mouse models.","[{'e1': 'HH ', 'e2': ' in mouse models.', 'relation': 'signaling in vivo ', 'condition': 'during PCa progression'}, {'e1': 'HH ', 'e2': 'during PCa progression', 'relation': 'signaling in vivo ', 'condition': ' in mouse models.'}]"
603,P83P6,"We have characterized the phenotype of the stromal cells in three mouse models of PCa – a probasin-driven MYC (PB-MYC) model, a conditional ERG and PTEN genetic model (ERG/PTEN), and a transgenic adenocarcinoma mouse prostate (TRAMP) model – and found that the proportions of cells with a smooth-muscle-like or fibroblast-like character were distinct in each of the three models. In PB-MYC and to a lesser extent ERG/PTEN, but not TRAMP tumors, SMCs are greatly depleted, recapitulating a loss of mature SMCs seen in human PCa. Using genetic fate mapping, we found that SMCs are largely lost without contributing to the fibroblast-like reactive stroma that is increased between ducts in PB-MYC tumors, but contribute to the expanded smooth muscle and also give rise to a specific subset of intraductal stromal cells in TRAMP tumors. We found that HH signaling is increased in stromal cells in all three models, especially those adjacent to tumor cells. In PB-MYC and TRAMP tumors, Ihh and Dhh rather than Shh are the main ligands expressed by tumor cells. In human PCa, IHH is the highest expressed of the three HH genes and the level of HH signaling positively correlates with the amount of stromal gene expression. To test whether stromal HH signaling can alter PCa progression, an activated form of the HH receptor was expressed in Gli1-expressing stromal cells of PB-MYC tumors. We found that excess HH signaling in prostate stromal cells has an inhibitory effect on cancer progression, potentially owing to maintenance of smooth muscle that might prevent micro-invasion of tumors. Our studies provide new insights into the heterogeneity of stromal cells in three mouse models and in human PCa, and into the possible importance of particular stromal cell types in tumor progression, and also identify the HH signaling pathway as a candidate of possible therapeutic value for treating PCa patients.","[{'e1': 'SMCs', 'e2': 'expanded smooth muscle', 'relation': 'contribute to', 'condition': 'in TRAMP tumors'}, {'e1': 'SMCs', 'e2': 'a specific subset of intraductal stromal cells', 'relation': 'give rise to', 'condition': 'in TRAMP tumors'}, {'e1': ' the level of HH signaling ', 'e2': 'the amount of stromal gene expression', 'relation': 'positively correlates with ', 'condition': ' In human PCa'}, {'e1': 'excess HH signaling ', 'e2': 'cancer progression', 'relation': 'has an inhibitory effect on', 'condition': 'in prostate stromal cells'}]"
604,P83P7,"In three mouse models of PCa, including one with highly recurrent mutations in human PCa (ERG/PTEN), we found distinct contributions of smooth-muscle-like and fibroblast-like cells to the stroma, yet HH signaling (Gli1nlacZ expression) was restricted to stromal cells, especially near the tumor epithelium. Whereas TRAMP tumors had an increase in SMCs and little change in interductal fibroblasts, PB-MYC, and to a lesser extent ERG/PTEN, had a decrease in SMCs and an accompanying increase in fibroblast-like stromal cells between the ducts. RNA-seq analysis of Gli1GFP-labeled cells of PB-MYC and normal prostate similarly revealed a major decrease in smooth muscle genes, and the fibroblast gene Vim was not altered. Based on the Human Protein Atlas and RNA data analysis, we confirmed that human PCa tumors have a dramatic disruption of the smooth muscle layers and a clear decrease in the mature smooth muscle marker calponin (CNN1) in advanced tumors, consistent with a previous report. ACTA2 staining revealed the smooth muscle layers were disrupted and the proportion of cells was decreased in most advanced tumor samples, whereas VIM was maintained in the remaining stromal cells. Analysis of TCGA, the largest RNA-seq dataset of primary PCa samples, revealed a decrease in ACTA2 and CNN1 but not VIM expression in more advanced tumors (higher Gleason score), suggesting the proportion of SMCs in human tumors, or at least the expression levels of the cell type-specific genes, are decreased. In a separate RNA expression dataset, ACTA2 and CNN1 but not VIM expression were found to be significantly lower in metastatic samples compared with primary tumors. In addition, we found correlations between higher luminal or lower basal cell gene expression and lower smooth muscle gene expression. Our study thus demonstrates that PCa in PB-MYC mice nicely models the decrease in smooth muscle layers seen in more advanced human PCa.","[{'e1': 'RNA-seq analysis of Gli1GFP-labeled cells of PB-MYC ', 'e2': 'a major decrease ', 'relation': 'similarly revealed ', 'condition': 'in smooth muscle genes'}, {'e1': 'normal prostate ', 'e2': 'a major decrease ', 'relation': 'similarly revealed ', 'condition': 'in smooth muscle genes'}, {'e1': ' human PCa tumors ', 'e2': 'the mature smooth muscle marker calponin (CNN1) ', 'relation': 'decrease in ', 'condition': 'in advanced tumors'}, {'e1': ' ACTA2 and CNN1', 'e2': 'metastatic samples compared with primary tumors', 'relation': 'were found to be significantly lower in ', 'condition': 'In a separate RNA expression dataset'}]"
605,P83P8,"Using genetic inducible fate mapping, we traced the fate of ACTA2-expressing cells in vivo during mouse tumor progression and found that the labeled cells are largely lost in PB-MYC tumors without changing fate and giving rise to cancer reactive stroma. In TRAMP tumors, in contrast, labeled SMCs not only expand the smooth muscle layers, but also contribute to cancer stromal cells, specifically in IAS and not between ducts. Thus, in TRAMP tumors, some labeled SMCs change their fate to fibroblasts and/or myofibroblast-like cells and migrate into IASs. However, SMCs in TRAMP tumors, as in PB-MYC tumors, do not contribute to interductal stromal cells. We propose that the fate of SMC is likely determined by the molecular character of the tumor epithelial cells. It will be interesting to determine if the cell of origin of interductal stroma is the stem or progenitor cell that a fate-mapping study indicates is restricted to the interductal fibroblast lineage. Furthermore, if each stromal lineage has a distinct expression signature, it should be possible to predict the cell of origin of reactive stroma in human PCa samples.","[{'e1': ' labeled SMCs ', 'e2': ' cancer stromal cells, ', 'relation': 'not only expand the smooth muscle layers but also contribute to', 'condition': 'specifically in IAS and not between ducts In TRAMP tumors'}, {'e1': ' some labeled SMCs ', 'e2': ' fibroblasts and/or myofibroblast-like cells and migrate into IASs', 'relation': 'change their fate to', 'condition': 'in TRAMP tumors'}]"
606,P84P1,"Hypermethylation of the paired-like homeodomain transcription factor 2 (PITX2) gene is a strong predictor of the risk of biochemical recurrence in patients with prostate cancer (PCa) after radical prostatectomy. We investigate whether PITX2 methylation is feasible for individualized risk assessment in prostate core biopsies before surgery. A quantitative, methylation-specific real-time PCR was used to measure PITX2 in three cohorts: i) matched samples of neoplastic and nonneoplastic tissue from 24 patients with PCa, ii) a well-characterized cohort of 300 patients with PCa after radical prostatectomy, and iii) core biopsy specimens from 32 patients with PCa and 31 patients with benign prostatic disease. PITX2 methylation discriminated between neoplastic and nonneoplastic tissue in patients with PCa. In the second cohort, PITX2 hypermethylation predicted an increased risk of biochemical recurrence in univariate Cox proportional hazards regression analysis and Kaplan-Meier analysis. In 753 prostate biopsies, 720 were applicable for analysis, rendering the assay feasible for diagnostic biopsies. PITX2 methylation was furthermore significantly increased in tumor-positive biopsies and strongly correlated with International Society of Urological Pathology grade groups. This study indicates that the PITX2 methylation assay is feasible in prostate biopsies and might add valuable prognostic information for risk assessment in a presurgical diagnostic setting.","[{'e1': 'Hypermethylation of the paired-like homeodomain transcription factor 2 (PITX2) gene ', 'e2': 'the risk of biochemical recurrence ', 'relation': 'is a strong predictor of ', 'condition': 'in patients with prostate cancer (PCa) after radical prostatectomy'}, {'e1': 'Hypermethylation of the paired-like homeodomain transcription factor 2 (PITX2) gene ', 'e2': 'the risk of biochemical recurrence in patients with prostate cancer (PCa)', 'relation': 'is a strong predictor of ', 'condition': 'after radical prostatectomy'}, {'e1': 'PITX2 methylation ', 'e2': 'neoplastic and nonneoplastic tissue', 'relation': 'discriminated between ', 'condition': ' in patients with PCa'}, {'e1': 'PITX2 hypermethylation', 'e2': 'increased risk of biochemical recurrence', 'relation': ' predicted an ', 'condition': ' in univariate Cox proportional hazards regression analysis and Kaplan-Meier analysis'}, {'e1': 'PITX2 methylation assay ', 'e2': 'feasible ', 'relation': 'is ', 'condition': 'in prostate biopsies '}, {'e1': 'PITX2 methylation assay ', 'e2': 'risk assessment ', 'relation': 'might add valuable prognostic information for ', 'condition': 'in a presurgical diagnostic setting.'}]"
607,P84P3,"The field of nucleic acid-based biomarkers offers a variety of marker candidates and technologies for standardized assays. With focus on the analysis of presurgical biopsy specimens, the limited amount of tissue represents a major technological challenge. DNA methylation seems to be a promising marker candidate with regard to this issue, allowing for robust measurements of stable DNA with limited input amount and viable implementation into clinical routine technologies. Epigenetic regulation via DNA methylation plays a key role in fundamental biological processes, such as cell differentiation and development. Moreover, DNA methylation is a hallmark of malignant tumors and is involved in the orchestration of carcinogenesis. This conceptual framework suggests that aberrantly methylated loci might be a valuable source for cancer biomarkers. So far, MGMT promoter methylation, which predicts progression-free survival in patients with glioblastoma multiforme undergoing therapy with temozolomide, has been used as the only routinely tested methylated biomarker in clinical practice.","[{'e1': 'Epigenetic regulation', 'e2': 'a key role ', 'relation': ' plays ', 'condition': 'in fundamental biological processes, such as cell differentiation and development'}, {'e1': 'DNA methylation', 'e2': 'malignant tumors and is involved', 'relation': ' is a hallmark of ', 'condition': ' in the orchestration of carcinogenesis'}, {'e1': 'MGMT promoter methylation ', 'e2': ' progression-free survival', 'relation': 'predicts', 'condition': ' in patients with glioblastoma multiforme undergoing therapy with temozolomide'}]"
608,P84P4,"The paired-like homeodomain transcription factor 2 (PITX2) gene, located on chromosome 4q25, encodes three isoforms (PITX2A, PITX2B, PITX2C) of bicoid transcription factors involved in embryonic development. Interestingly, PITX2 has also been identified as an upstream regulator of the insulin-like growth factor 1 receptor and androgen receptor in prostate cancer, indicating an important role in prostate carcinogenesis. Previous studies have found that aberrant PITX2 methylation is a strong prognostic marker for disease progression in not only breast and lung cancer but also prostate cancer. In PCa, several studies have found that PITX2 hypermethylation is an independent prognosticator of biochemical recurrence after radical prostatectomy; however, none of these studies were conducted on biopsy specimens. This finding prompted us to investigate whether PITX2 methylation can also serve as a feasible assay for individualized risk assessment of PCa in diagnostic core biopsies before surgery.","[{'e1': 'PITX2 ', 'e2': 'the insulin-like growth factor 1 receptor and androgen receptor ', 'relation': 'has also been identified as an upstream regulator of ', 'condition': 'in prostate cancer, indicating an important role in prostate carcinogenesis'}, {'e1': 'PITX2 hypermethylation ', 'e2': ' biochemical recurrence ', 'relation': 'is an independent prognosticator of', 'condition': 'after radical prostatectomy'}]"
609,P84P5,"In several previous studies, PITX2 methylation has exhibited its potential as a prognostic biomarker. In breast cancer, the PITX2 promoter hypermethylation was associated with poor outcome and higher recurrence risk regardless of given therapies. In patients with PCa treated with radical prostatectomy, two large studies with independent patient cohorts revealed an association of PITX2 hypermethylation with a higher risk of biochemical recurrence. A diagnostic microarray and a qPCR assay were developed and validated to provide clinicians with technologies that are more applicable for routine diagnostics. In the present study, we investigated whether PITX2 methylation assessed using qPCR can also serve as a feasible assay for individualized risk assessment of PCa in core biopsies before surgery.","[{'e1': 'the PITX2 promoter hypermethylation ', 'e2': 'poor outcome and higher recurrence risk', 'relation': 'was associated with ', 'condition': ' In breast cancer'}, {'e1': ' PITX2 hypermethylation ', 'e2': 'a higher risk of biochemical recurrence', 'relation': 'is associated with', 'condition': ' In patients with PCa treated with radical prostatectomy'}, {'e1': 'PITX2 promoter hypermethylation', 'e2': 'poor outcome and higher recurrence risk', 'relation': 'was associated with', 'condition': 'in breast cancer'}]"
610,P84P9,"Notably, there was a slight but significant difference between biopsy samples from patients with benign prostatic disease and tumor-negative samples of patients with PCa. This finding might indicate the presence of undetected preneoplasia or a field effect. Multiple biomarkers identifying cytomorphologic, genetic, epigenetic, and expression abnormalities in putatively normal prostatic tissue have been identified, which support the existence of a field effect in prostate carcinogenesis.","[{'e1': 'Multiple biomarkers ', 'e2': 'the existence of a field effect ', 'relation': 'support ', 'condition': 'in prostate carcinogenesis.'}]"
611,P85P6,"An estimated 50,000 radical prostatectomies are performed each year in the US, and about 15,000 of these patients will experience biochemical recurrence. Here we show that a four-gene signature based on HBEGF, HOXC13, IGFBP2, and SATB1 was able to identify patients whose prostate cancer recurred. The prediction algorithm that incorporated surgical information provided accurate prognostic information on patient outcomes with 83% accuracy. Most patients undergoing radical prostatectomy receive no additional treatment beyond regular monitoring of PSA. Adjuvant radiotherapy administered immediately after radical prostatectomy could improve outcomes for patients identified using the CRG signature to be at high risk for recurrence.","[{'e1': 'Adjuvant radiotherapy administered ', 'e2': 'patients identified using the CRG signature to be at high risk for recurrence.', 'relation': 'could improve outcomes for ', 'condition': 'immediately after radical prostatectomy '}]"
612,P85P7,"The four genes identified in our signature, HBEGF, HOXC13, IGFBP2, and SATB1, all play significant roles in the modification of cancer phenotypes. HOXC13, a homeobox-family transcription factor known to control cell proliferation and differentiation, was found to be upregulated in our recurrent prostate cancer samples. HOXC13 has been reported to be upregulated in metastatic melanoma compared to primary tumor tissue. Furthermore, knockdown of HOXC13 has been reported to decrease viability of several cancer cell lines in vitro, including the prostate cancer line PC-3ML. SATB1 is a chromatin organizer responsible for the recruitment of chromatin remodeling proteins, and was found to be downregulated in our recurrent sample cohort. In colorectal cancer, loss of SATB1 was reported to be a strong predictor of worse outcomes. Publicly available microarray data indicates that SATB1 is downregulated in prostate cancer as well as other solid tumors. Increased nuclear localization of SATB1 has been reported to be correlated with increased prostate cancer aggression and invasive potential. Although this runs counter to our observation, it is possible that our recurrent prostate cancer samples may have higher nuclear localization despite lower overall expression. The appearance of IGFBP2 in our gene signature was reassuring, since decreased expression of this gene has been reported to be a predictor of prostate cancer recurrence after radical prostatectomy. The structurally similar protein IGFBP5 has also been found to be downregulated in metastatic prostate cancer. Finally, HBEGF is a ligand of the EGF receptor that also binds heparin. HBEGF has not been studied in prostate cancer, but HBEGF is known to promote invasion and metastasis in breast, colon, and ovarian cancer. HBEGF was unexpectedly downregulated in the recurrent prostate cancer samples, which would appear at odds with its previously documented role in cancer. However, a recent study found that the expression of the growth factor receptor FGFR1 was associated with indolent prostate cancer. While the particular mechanism by which FGFR1 acts to drive this outcome is unknown, HBEGF may function in a similar way.","[{'e1': 'HOXC13 ', 'e2': 'upregulated ', 'relation': 'was found to be ', 'condition': 'in our recurrent prostate cancer samples'}, {'e1': ' HOXC13', 'e2': 'upregulated in metastatic melanoma ', 'relation': ' has been reported to be', 'condition': 'compared to primary tumor tissue'}, {'e1': 'SATB1 ', 'e2': 'downregulated ', 'relation': 'was found to be ', 'condition': 'in our recurrent sample cohort'}, {'e1': 'loss of SATB1 ', 'e2': ' a strong predictor of worse outcomes', 'relation': 'was reported to be', 'condition': ' In colorectal cancer'}, {'e1': 'decreased expression of this gene ', 'e2': ' a predictor of prostate cancer recurrence ', 'relation': 'has been reported to be', 'condition': 'after radical prostatectomy'}, {'e1': 'The structurally similar protein IGFBP5 ', 'e2': 'downregulated', 'relation': 'has also been found to be ', 'condition': ' in metastatic prostate cancer'}, {'e1': 'HBEGF ', 'e2': 'invasion and metastasis', 'relation': 'is known to promote ', 'condition': ' in breast cancer'}, {'e1': 'HBEGF ', 'e2': 'invasion and metastasis', 'relation': 'is known to promote ', 'condition': 'in colon cancer'}, {'e1': 'HBEGF ', 'e2': 'invasion and metastasis', 'relation': 'is known to promote ', 'condition': 'in ovarian cancer'}, {'e1': 'HBEGF ', 'e2': 'downregulated ', 'relation': 'was unexpectedly ', 'condition': 'in the recurrent prostate cancer samples'}, {'e1': 'knockdown of HOXC13 ', 'e2': 'viability of several cancer cell lines', 'relation': 'has been reported to decrease ', 'condition': ' in vitro, including the prostate cancer line PC-3ML'}]"
613,P85P8,"The focus for this study was biochemical recurrence after radical prostatectomy. Biochemical recurrence after prostatectomy almost always requires the primary tumor to already have escaped the prostatic capsule, either invading local tissue or metastasizing to regional lymph nodes or distant organs. These behaviors are hallmarks of tumor aggressiveness, and suggest that the CRG signature may provide valuable information for assessing patient outcomes even in patients who have not undergone radical prostatectomy. Currently the best test to determine risk of aggressive disease is the Gleason score, a test with limited predictive power in many cases. Several groups have already identified gene signatures that are hallmarks of either indolent or aggressive disease. The CRG signature, which is predictive of biochemical recurrence of prostate cancer, could likewise provide useful prognostic information to patients at the point of diagnosis, and further tests should be conducted to evaluate this possibility. This would, however, necessitate the use of formalin-fixed, paraffin-embedded biopsy tissue.","[{'e1': 'Biochemical recurrence ', 'e2': ' the primary tumor to already have escaped the prostatic capsule', 'relation': 'almost always requires', 'condition': 'after prostatectomy'}]"
614,P85P9,"Irshad et al. identified a three-gene signature associated with aging and cellular senescence that is predictive of indolence in prostate cancer with low Gleason grades. These low-grade cancers are often managed with active surveillance, however, not all of them are indolent. Identifying patients who would typically not be treated aggressively who do in fact require an intervention is also the focus of our study. Likewise, Ross-Adams et al. identified a 100-gene panel predictive of prostate cancer recurrence using a transcriptomics approach. The indolence signature and the transcriptomics signature may complement the recurrence signature reported herein; combining these different approaches may lead to better prediction of prostate cancer outcomes.","[{'e1': 'a three-gene signature ', 'e2': 'aging and cellular senescence ', 'relation': 'associated with ', 'condition': 'in prostate cancer with low Gleason grades'}]"
615,P86P19,"We took advantage of the possibility to uniformly assess several other histopathological features which could potentially serve as future prognostic factors. We then divided the patients in men with PSA response or stable PSA and men with rapid biochemical progression in the early phase of follow-up after salvage RT and identified the largest diameter of carcinoma to be independently associated with rising PSA after salvage RT. Patients with rapid biochemical progression likely harbor micrometastatic disease or radioresistant disease and may benefit from more tailored treatment e.g. addition of androgen deprivation therapy (ADT). The prognostic significance of largest diameter of carcinoma has been described controversially, some have described it as independent prognostic factor others as less important. Once our trial will have mature biochemical control results we will repeat the analysis to identify prognostic factors and might be able to include some of the histopathological features in a Nomogram. No relevant differences in largest diameter of carcinoma were observed between the two treatment arms.","[{'e1': 'the largest diameter of carcinoma ', 'e2': 'rising PSA ', 'relation': 'to be independently associated with ', 'condition': 'after salvage RT'}]"
616,P86P22,"The results of the central pathology analyses revealed discordant results for seminal vesicle invasion, extraprostatic extension, positive surgical margin as well as Gleason score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT.","[{'e1': 'Largest diameter of carcinoma ', 'e2': 'potential prognostic factor for rapid biochemical progression', 'relation': 'was found to be a ', 'condition': ' after salvage RT.'}]"
617,P86P3,"There was good concordance between central pathology review and local pathologists for seminal vesicle invasion [pT3b: 91%; k = 0.95 (95% CI 0.89, 1.00)], for extraprostatic extension [pT3a/b: 94%; k = 0.82 (95% CI 0.75, 0.89)], and for positive surgical margin status [87%; k = 0.7 (95% CI 0.62, 0.79)]. Agreement was lower for Gleason score [78%; k = 0.61 (95% CI 0.52, 0.70)]. The median largest diameter of carcinoma was 16 mm (range, 3–38 mm). A total of 49 patients (18%) experienced rapid biochemical progression after salvage RT. Largest diameter of carcinoma [odds ratio (OR): 2.04 (95% Confidence interval (CI): 1.30, 3.20); p = 0.002], resection margin status [OR: 0.36 (95% CI: 0.18, 0.72); p = 0.004] and Gleason score [OR: 1.55 (95% CI: 1.00, 2.42); p = 0.05] remained associated with rapid progression after salvage RT after backward selection.","[{'e1': '49 patients (18%) ', 'e2': 'rapid biochemical progression ', 'relation': 'experienced ', 'condition': 'after salvage RT'}, {'e1': 'largest diameter of carcinoma', 'e2': 'rapid progression', 'relation': 'remained associated with', 'condition': 'after salvage RT'}, {'e1': 'resection margin status', 'e2': 'rapid progression', 'relation': 'remained associated with', 'condition': 'after salvage RT'}, {'e1': 'Gleason score', 'e2': 'rapid progression', 'relation': 'remained associated with', 'condition': 'after salvage RT'}]"
618,P86P4,"The results of the central pathology analyses reveal concordant results for seminal vesicle invasion, extraprostatic extension, positive surgical margin but lower agreement for Gleason Score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT.","[{'e1': 'Largest diameter of carcinoma ', 'e2': 'rapid biochemical progression ', 'relation': 'was found to be a potential prognostic factor for ', 'condition': 'after salvage RT.'}]"
619,P86P5,"Patients with biochemical recurrence after prostatectomy without evidence of distant metastatic disease commonly undergo early salvage radiation therapy (RT) of the prostate bed as their major curative treatment approach. There are several established pathological features such as the Gleason Score, tumor classification and resection margin status which can serve as prognostic factors for the outcome after salvage RT and thus must be assessed in a standardized fashion. However, it has been previously described that these factors could significantly vary when being assessed by dedicated genitourinary pathologist in a central pathology review. This may influence the outcome analyses of clinical trials and therefore the use of central pathology reviews is recommended.","[{'e1': 'Patients with biochemical recurrence ', 'e2': 'early salvage radiation therapy (RT) of the prostate bed as their major curative treatment approach', 'relation': 'commonly undergo ', 'condition': 'after prostatectomy without evidence of distant metastatic disease'}, {'e1': ' several established pathological features', 'e2': 'prognostic factors for the outcome', 'relation': ' serve as ', 'condition': ' after salvage RT'}]"
620,P86P7,It has been described that around one fifth of patients experience rapid biochemical progression after RT and these patients may harbor micrometastatic or radioresistant disease and may require a more tailored treatment approach. Thus it it appears to be important to search for clinical and histopathological predictors for rapid biochemical progression.,"[{'e1': 'around one fifth of patients ', 'e2': 'rapid biochemical progression ', 'relation': 'experience ', 'condition': 'after RT'}]"
621,P86P8,We describe here the differences between the central and local pathology results for patients treated within our clinical trial on salvage RT and analyze the association of several histopathological features and rapid biochemical progression after salvage RT.,"[{'e1': ' several histopathological features ', 'e2': 'rapid biochemical progression ', 'relation': 'associated with', 'condition': 'after salvage RT.'}]"
622,P86P9,"The results of the present central pathology review analysis confirmed a good concordance for major histopathological prognostic factors such as seminal vesicle invasion, extraprostatic extension, positive surgery margin but lower agreement for Gleason Score. Additionally, we could identify the diameter of largest carcinoma as a potential prognostic factor for rapid biochemical progression after salvage RT.","[{'e1': 'the diameter of largest carcinoma ', 'e2': ' rapid biochemical progression ', 'relation': 'as a potential prognostic factor for', 'condition': 'after salvage RT.'}]"
623,P87P1,"Activation of the Canonical Wnt pathway (CWP) has been linked to advanced and metastatic prostate cancer, whereas the Wnt5a-induced non-canonical Wnt pathway (NCWP) has been associated with both good and poor prognosis. A newly discovered NCWP, Wnt5/Fzd2, has been shown to induce epithelial-to-mesenchymal transition (EMT) in cancers, but has not been investigated in prostate cancer. The aim of this study was to investigate if the CWP and NCWP, in combination with EMT, are associated with metabolic alterations, aggressive disease and biochemical recurrence in prostate cancer. An initial analysis was performed using integrated transcriptomics, ex vivo and in vivo metabolomics, and histopathology of prostatectomy samples (n=129), combined with at least five-year follow-up. This analysis detected increased activation of NCWP through Wnt5a/Fzd2 as the most common mode of Wnt activation in prostate cancer. This activation was associated with increased expression of EMT markers and higher Gleason score. The transcriptional association between NCWP and EMT was confirmed in five other publicly available patient cohorts (1519 samples in total). A novel gene expression signature of concordant activation of NCWP and EMT (NCWP-EMT) was developed, and this signature was significantly associated with metastasis and shown to be a significant predictor of biochemical recurrence. The NCWP-EMT signature was also associated with decreased concentrations of the metabolites citrate and spermine, which have previously been linked to aggressive prostate cancer. Our results demonstrate the importance of NCWP and EMT in prostate cancer aggressiveness, suggest a novel gene signature for improved risk stratification, and give new molecular insight.","[{'e1': 'Wnt5/Fzd2 ', 'e2': 'epithelial-to-mesenchymal transition (EMT) ', 'relation': 'has been shown to induce ', 'condition': 'in cancers'}, {'e1': 'the CWP and NCWP, in combination with EMT ', 'e2': 'metabolic alterations', 'relation': 'are associated with ', 'condition': 'in prostate cancer'}, {'e1': 'the CWP and NCWP, in combination with EMT ', 'e2': 'aggressive disease ', 'relation': 'are associated with ', 'condition': 'in prostate cancer'}, {'e1': 'the CWP and NCWP, in combination with EMT ', 'e2': 'biochemical recurrence ', 'relation': 'are associated with ', 'condition': 'in prostate cancer'}]"
624,P87P10,"We further investigated alterations in the CWP between low Gleason and high Gleason samples. There were no significant gene expression alterations detected for β-catenin, the Wnt ligands, the receptor-complex and the destruction complex. Of the CWP inhibitors, both SFRP2 and SFRP4 were upregulated in high Gleason compared to low Gleason cancer samples, which is contradictory to CWP activation. However, the inhibitor of β-catenin translocation, ICAT, was downregulated, and the CWP transcription factors LEF1 and TCF were upregulated in high Gleason cancer, which could indicate activation of downstream components of the pathway independently of the β-catenin destruction complex. To conclude, the overall analysis suggests no significant increase in CWP activation through the canonical destruction complex, neither in cancer compared to normal nor in high Gleason cancer.","[{'e1': 'SFRP2 and SFRP4 ', 'e2': 'in high Gleason cancer samples', 'relation': 'were upregulated', 'condition': 'compared to low Gleason cancer samples'}]"
625,P87P11,"There is currently no consensus in the literature regarding CWP activation in prostate cancer, and our findings are contradictory to several previous studies suggesting increased CWP in prostate cancer. The CWP has previously been associated with advanced disease such as androgen resistant prostate cancer in cell lines, and prostate cancer bone metastasis in human tissue and cell lines. The fact that our cohorts consist of radical prostatectomy tissue, from localized or locally advanced disease, may explain the absence of CWP activation. The CWP may therefore still be of importance in advanced, metastatic prostate cancer, but might not prove useful for early risk stratification. Furthermore, several previous studies reporting increased CWP signaling were using prostate cancer cell lines. The disparity could therefore also highlight a difference between in vitro cell lines and human prostate tissue, emphasizing the importance of validation studies in human tissue, especially for identification of potential targets for personalized drug therapy.","[{'e1': 'the CWP', 'e2': 'prostate cancer bone metastasis', 'relation': 'has previously been associated with', 'condition': 'in human tissue and cell lines'}]"
626,P87P15,"Wnt5a has been suggested as a biomarker in prostate cancer, but its prognostic outcome has been inconsistent. The increased WNT5A gene expression in high Gleason cancer samples compared to low Gleason samples is in agreement with results from Yamamoto et al. who reported increased Wnt5a IHC staining of prostatectomy tissue samples with high Gleason grade. This oncogenic effect of Wnt5a in prostate cancer progression is also supported by studies of cell lines, where Wnt5a has been shown to improve migration capacity, induce androgen resistance in prostate cancer metastases, and induce bone metastasis. Contrary to this, other IHC studies of prostatectomy tissue samples have detected a tumor-suppressing role of Wnt5a in prostate cancer; increased Wnt5a IHC expression has been associated with increased 10 years survival, and a lower risk of biochemical recurrence. This was, however, only true for low Gleason grade samples in one of the studies. This apparent opposing role of Wnt5a in prostate cancer may be explained by the paradoxical effect of Wnt5a in other cancers. In melanoma, pancreatic and gastric cancer, Wnt5a expression is associated with worse prognosis, but in colon and thyroid cancer Wnt5a expression is associated with better prognosis. The tumor-promoting role of Wnt5a can be caused by activation of NCWP, whereas the tumor-suppressing role may be caused by inhibition of the CWP. Because of this conflicting role in different cancer types, we suspect that Wnt5a alone may not be a useful biomarker for prostate cancer.","[{'e1': 'Wnt5a ', 'e2': 'a biomarker ', 'relation': 'has been suggested as ', 'condition': 'in prostate cancer'}, {'e1': 'IHC studies of prostatectomy tissue samples ', 'e2': 'a tumor-suppressing role of Wnt5a ', 'relation': 'have detected ', 'condition': 'in prostate cancer'}, {'e1': ' Wnt5a expression ', 'e2': 'worse prognosis', 'relation': 'is associated with ', 'condition': 'In melanoma cancer'}, {'e1': ' Wnt5a expression ', 'e2': 'worse prognosis', 'relation': 'is associated with ', 'condition': 'in pancreatic cancer'}, {'e1': ' Wnt5a expression ', 'e2': 'worse prognosis', 'relation': 'is associated with ', 'condition': 'in gastric cancer'}, {'e1': ' Wnt5a expression ', 'e2': 'better prognosis', 'relation': 'is associated with ', 'condition': 'in colon cancer'}, {'e1': ' Wnt5a expression ', 'e2': 'better prognosis', 'relation': 'is associated with ', 'condition': 'in thyroid cancer'}]"
627,P87P2,"Increased activation of the Wnt signaling pathway (WP) is associated with development, progression, and metastasis of many cancers. In prostate cancer, the WP has been associated with aggressive, late stage disease, and metastasis; however, its potential for early prediction of aggressiveness is still unclear. Previous studies are mainly performed in prostate cancer cell lines, and proper validation in human tissue is lacking. The WP is proposed as a therapeutic target in prostate cancer treatment, and reduced proliferation has been detected as a result of targeted Wnt-inhibitor drugs in cell lines. However, to develop Wnt-targeted drugs for human prostate cancer, an increased understanding of the molecular mechanisms in vivo is needed.","[{'e1': ' the WP ', 'e2': ' aggressive, late stage disease, and metastasis', 'relation': 'has been associated with', 'condition': 'In prostate cancer'}]"
628,P87P20,"Decreased concentrations of citrate and spermine have been associated with aggressive prostate cancer, and our results therefore suggest the NCWP-EMT signature to be associated with an aggressive metabolic profile. Reduced citrate can be a result of increased energy production through the Krebs cycle in prostate cancer. Previously, Wnt5a signaling has been identified as a regulator of the energy metabolism in melanoma cancer cells, and alterations of this metabolism have also been associated with EMT in cancer. Another study detected that reduced polyamine content promoted EMT in non-tumor cells. We therefore hypothesize that NCWP-EMT activation is associated with alterations in citrate and spermine metabolism in prostate cancer, although the direct mechanisms require further investigation.","[{'e1': 'Reduced citrate ', 'e2': 'increased energy production ', 'relation': 'can be a result of ', 'condition': 'through the Krebs cycle in prostate cancer'}, {'e1': 'Wnt5a signaling ', 'e2': 'the energy metabolism ', 'relation': 'has been identified as a regulator of ', 'condition': 'in melanoma cancer cells'}, {'e1': 'alterations of this metabolism ', 'e2': 'EMT ', 'relation': 'have also been associated with ', 'condition': 'in cancer'}, {'e1': 'NCWP-EMT activation ', 'e2': 'alterations in citrate and spermine metabolism ', 'relation': 'is associated with ', 'condition': 'in prostate cancer'}, {'e1': ' reduced polyamine content', 'e2': ' EMT ', 'relation': ' promoted', 'condition': 'in non-tumor cells'}]"
629,P87P21,"To investigate the potential clinical translation of the metabolic findings, we inspected the gene signature score with matched pre-surgical in vivo MRSI from the same patients. Reduced citrate/creatine and spermine/creatine ratios were detected for high NCWP-EMT score samples when compared with low NCWP-EMT score. Although we had a limited number of matched samples in the main cohort, the results support our findings from the tissue analysis, and demonstrates that the MR biomarkers can reflect the NCWP-EMT signature also in non-invasive MRSI examinations.","[{'e1': 'MR biomarkers ', 'e2': 'the NCWP-EMT signature ', 'relation': 'can reflect ', 'condition': 'in non-invasive MRSI examinations.'}]"
630,P87P22,"Citrate and spermine are stored within the luminal space of the glands in prostate tissue, and the observed metabolic alterations can be due to cell metabolism or morphological changes. In the main cohort, the citrate and spermine concentrations were correlated with luminal space. This was a weaker correlation than between citrate and spermine concentrations and the NCWP-EMT signature score. Linear mixed modeling, adjusting for luminal space as well as other tissue heterogeneity and Gleason score, still showed the same metabolic alterations to be significant. These results suggest the alterations observed in citrate and spermine concentrations are a combination of changes in both luminal space and reprogramming of metabolism in samples with high NCWP-EMT score. There was no relationship between Wnt5a expression and metabolite concentrations in either the main or immunohistochemistry cohort. This supports that Wnt5a should be used as a biomarker in combination with other pathway components, such as our NCWP-EMT signature.","[{'e1': 'Citrate and spermine ', 'e2': 'luminal space of the glands', 'relation': 'are stored within the ', 'condition': ' in prostate tissue'}, {'e1': ' the citrate and spermine concentrations ', 'e2': 'luminal space', 'relation': 'were correlated with ', 'condition': 'In the main cohort'}]"
631,P87P23,"In the main cohort the five-year biochemical recurrence free rates were 100%, 75% and 46% for the patients in the low, intermediate and high NCWP-EMT score groups, respectively, and the Kaplan-Meier plot showed a significant separation between the groups. Validation of recurrence was possible in the GSE21034 cohort and showed a similar pattern with 10-year biochemical recurrence free rates of 81%, 73% and 57% in patients with low, intermediate and high NCWP-EMT score, respectively. However, there was no significant separation in the Kaplan-Meier curves for this cohort. For this validation dataset there was only one sample per patient, not necessarily extracted from the most aggressive cancer foci, which may reduce the precision of the NCWP-EMT grouping for biochemical recurrence analysis. In addition, many of the patients in the validation dataset were lost to follow-up early, and therefore censored in the analysis, causing reduced reliability of the curves. In the GSE46691 cohort, samples with high NCWP-EMT scores were significantly associated with metastases. With the significant separation in our data, and the similar trend in the validation datasets, we therefore suggest that increased NCWP-EMT signature score is associated with an increased risk of biochemical recurrence and metastases. This strengthens the NCWP-EMT signature, and the activation of the Wnt5/Fzd2 pathway, as markers of aggressive prostate cancer.","[{'e1': ' samples with high NCWP-EMT scores ', 'e2': 'metastases', 'relation': 'were significantly associated with ', 'condition': 'In the GSE46691 cohort'}]"
632,P87P26,"The present study showed no alterations in the CWP in prostate cancer, but revealed an increased expression of NCWP and EMT markers in a subgroup of mainly high Gleason grade prostate cancer samples. A novel gene expression signature (NCWP-EMT) for this expression profile was presented and confirmed in several publicly available patient cohorts. High NCWP-EMT score was associated with reduced concentrations of the metabolites citrate and spermine both ex vivo, and in a clinical non-invasive setting using in vivo patient MRSI. The novel NCWP-EMT signature was also shown to be a predictor of biochemical recurrence and was associated with metastasis, indicating that upregulation of the NCWP and EMT is linked to more aggressive prostate cancer. The novel NCWP-EMT signature may therefore be useful for risk stratification and molecular subtyping of prostate cancer patients. The NCWP and its relation to EMT, cancer aggressiveness and tumor metabolism warrants further attention in prostate cancer studies.","[{'e1': 'high NCWP-EMT score', 'e2': 'reduced concentrations of citrate and spermine', 'relation': 'was associated with', 'condition': 'in a clinical non-invasive setting using in vivo patient MRSI'}]"
633,P87P3,"Wnt ligands bind to Frizzled (Fzd) receptors to activate the WP, which then induces signal transduction cascades. The WP is generally divided into a β-catenin-dependent canonical WP (CWP), and a β-catenin-independent non-canonical WP (NCWP). The importance of the CWP in carcinogenesis was first discovered in colorectal cancer, where mutations of the APC gene, a part of the β-catenin destruction complex, resulted in stabilization and nuclear translocation of β-catenin. This β-catenin translocation is a hallmark of CWP activation, and can drive tumor invasion and metastasis through a process of epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cancer cells develop into less adhesive and more motile mesenchymal-like cells, which increases the cancer’s potential for invasion and metastasis. There is mounting evidence associating EMT in prostate cancer with increased aggressiveness. Several studies support the activation of CWP in advanced and metastatic prostate cancer, but little evidence exists for localized and locally advanced prostate cancer.","[{'e1': 'mutations of the APC gene ', 'e2': 'stabilization of β-catenin', 'relation': 'resulted in ', 'condition': ' in colorectal cancer'}, {'e1': 'mutations of the APC gene ', 'e2': 'nuclear translocation of β-catenin', 'relation': 'resulted in ', 'condition': ' in colorectal cancer'}, {'e1': 'β-catenin translocation ', 'e2': 'tumor invasion and metastasis ', 'relation': 'can drive ', 'condition': 'through a process of epithelial-to-mesenchymal transition (EMT)'}, {'e1': 'EMT', 'e2': ' with increased aggressiveness', 'relation': 'is associated with', 'condition': 'in prostate cancer '}]"
634,P87P4,"The NCWP is commonly divided into two pathways, the planar cell polarity (PCP), and the Wnt/Calcium pathway. Few studies have addressed the significance of NCWP in prostate cancer. Most attention has been focused on the role of the non-canonical ligand Wnt5a, a key activator of the NCWP. Wnt5a is generally found to be upregulated in prostate cancer, but results are inconsistent regarding its association with good or poor prognosis. Recently, a new NCWP involving Wnt5a and the receptor Frizzled2 (Fzd2) was discovered and shown to promote tumor progression and EMT in several cancer cell lines and a mouse xenograft model. In the same study, a Wnt5/Fzd2 based gene set was also shown to accurately predict metastasis and survival in a small cohort of patients with hepatocellular carcinoma. However, this study did not address the in vivo relevance of the NCWP in larger patient cohorts or in prostate cancer tissue.","[{'e1': 'Wnt5a ', 'e2': 'upregulated ', 'relation': 'is generally found to be ', 'condition': 'in prostate cancer'}]"
635,P87P5,"Metabolic reprogramming is a hallmark of cancer, and the WP has been suggested as an emerging mediator of cancer cell metabolism. Wnt5a-mediated NCWP has been directly related to alterations of the energy metabolism in melanoma and breast cancer cells. Selected metabolic alterations detected in tissue samples by high resolution magic angle spinning magnetic resonance spectroscopy can be translated for use in a clinical setting by magnetic resonance spectroscopy imaging. Differences in (choline + creatine + spermine)/citrate ratio between low and high histopathological Gleason score have previously been detected using in vivo MRSI of patients, and citrate and spermine are suggested as the main contributors to discriminating on the basis of tumor aggressiveness from tissue HR-MAS MRS analysis. To date, metabolic alterations associated with the WP have not been investigated in prostate cancer.","[{'e1': 'Wnt5a-mediated NCWP ', 'e2': 'alterations of the energy metabolism ', 'relation': 'has been directly related to ', 'condition': 'in melanoma and breast cancer cells'}]"
636,P87P8,"To investigate if the CWP is activated in prostate cancer, we compared gene expression of the central CWP genes between cancer and normal samples of the main cohort using sample subsets balanced and unbalanced for stroma content according to histopathology. The level of β-catenin, the key component of the CWP pathway, showed no significant altered expression in cancer compared to normal, and two of the main components of the β-catenin destruction complex, GSK3B and AXIN1, were significantly upregulated in cancer. This may suggest increased activity of β-catenin destruction in prostate cancer, contrary to what is expected when the CWP is turned on. Additionally, the Wnt ligand genes associated with the CWP were not significantly changed in cancer compared to normal samples. Other important findings are reduced expression of the receptor FZD1, increased expressions of the antagonist SFRP4 and casein kinase CSNK1E, which support the absence of CWP activation. Although some variations were observed, the lack of upregulation of the main CWP genes suggests no increased expression activity of the CWP in prostate cancer in our main cohort.","[{'e1': ' GSK3B and AXIN1', 'e2': ' upregulated ', 'relation': 'were significantly', 'condition': 'in cancer'}]"
637,P88P10,"Here, using two large prostate cancer patient cohorts, we identified and independently validated RHCG, TCAF1, and the 2-gene panel RHCG-TCAF1 as novel independent adverse predictors of biochemical recurrence after radical prostatectomy. Prior to this, only a few candidate methylation markers have demonstrated prognostic potential in more than one prostate cancer cohort by multivariate analysis adjusting for established clinicopathological parameters. These are PITX2, GABRE-miR-452-miR-224, C1orf114, and the panels C1orf114/HAPLN3 and AOX1/C1orf114/HAPLN3. Further studies, using large independent cohorts with long follow-up, are needed to assess the clinical utility of RHCG and TCAF1 as well as of the previously identified prognostic methylation marker candidates. These candidates should be investigated individually, as well as in combinations, to identify their true prognostic potential.","[{'e1': 'RHCG', 'e2': 'a novel independent adverse predictor of biochemical recurrence', 'relation': 'was identified and independently validated as', 'condition': 'after radical prostatectomy'}, {'e1': 'TCAF1', 'e2': 'a novel independent adverse predictor of biochemical recurrence', 'relation': 'was identified and independently validated as', 'condition': 'after radical prostatectomy'}, {'e1': 'the 2-gene panel RHCG-TCAF1', 'e2': 'a novel independent adverse predictor of biochemical recurrence', 'relation': 'was identified and independently validated as', 'condition': 'after radical prostatectomy'}]"
638,P88P13,"The potential functional roles of our 8 candidate methylation markers in prostate physiology and malignancy are largely unknown. Here, we found that expression of 6 of these genes was significantly downregulated in prostate cancer, consistent with epigenetic silencing and suggesting a possible function in prostate carcinogenesis and or tumor progression. More specifically, we observed promoter hypermethylation and downregulation of RHCG in prostate tumors, which is consistent with previous reports of RHCG downregulation in kidney and oesophageal carcinomas. RHCG encodes an epithelial ammonia transporter that is widely expressed in the kidney, liver and intestinal tract, as well as in male reproductive organs, where it contributes to multiple components of fertility. The role of RHCG in the normal and cancerous prostate, however, is unknown and further studies are warranted.","[{'e1': 'RHCG', 'e2': 'multiple components of fertility', 'relation': 'contributes to', 'condition': 'in male reproductive organs'}]"
639,P88P14,"TCAF1 was recently identified as a positive regulator of TRPM8, an ionotropic testosterone receptor highly expressed in various organs, including the prostate, but its exact function in the prostate is unknown. According to our analysis, TCAF1 expression was unaltered or modestly upregulated in localized prostate tumors compared to non-malignant prostate tissue samples, consistent with a previous study. Several studies have reported that intragenic DNA methylation, as we observed for TCAF1 in prostate cancer, is involved in alternative transcription start site regulation in normal and malignant tissue. Moreover, gene body methylation is a feature of actively transcribed genes. Future studies should investigate TCAF1 methylation and potential isoform-specific expression patterns in non-malignant and malignant prostate cells to elucidate its possible role in prostate cancer tumorigenesis and progression.","[{'e1': ' intragenic DNA methylation ', 'e2': 'alternative transcription start site regulation ', 'relation': 'is involved in ', 'condition': 'in normal and malignant tissue'}]"
640,P88P17,"Moreover, the radical prostatectomy cohorts used for analysis of prognostic biomarker potential were of moderately different compositions, with patients in cohort 1 suffering more biochemical recurrences and having tumors with higher pathological tumor stage and higher median pre-operative PSA compared to patients in cohort 2. Nevertheless, all routine clinicopathological variables were significant predictors of biochemical recurrence in uni- and multivariate Cox regression analysis in both cohorts, strongly indicating that both constitute representative radical prostatectomy cohorts. Moreover, our RHCG-TCAF1 panel was significant in multivariate analysis in both cohorts, using the exact numerical dichotomization and trichotomization cut-points derived from cohort 1, indicating the robustness of our methylation marker candidates.","[{'e1': 'all routine clinicopathological variables ', 'e2': ' biochemical recurrence ', 'relation': 'were significant predictors of', 'condition': 'in uni- and multivariate Cox regression analysis in both cohorts'}]"
641,P88P18,"Another limitation to our study is the lack of surgical margin status information for most patients in cohort 2, thus this parameter was excluded from multivariate analysis in this cohort. Nevertheless, surgical margin status was a significant predictor of biochemical recurrence in uni- and multivariate Cox regression analysis in cohort 1, as were our methylation marker candidates, further supporting their strength as independent prognostic biomarkers for prostate cancer. Furthermore, the use of biochemical recurrence as end-point for survival analysis constitutes another possible limitation. Biochemical recurrence may result from either non-radical surgery, or micrometastatic disease manifesting prior to surgery, and is only a surrogate marker for tumor aggressiveness. Thus, future studies should investigate our novel methylation marker candidates in relation to more clinically relevant endpoints, such as metastatic progression or prostate cancer-specific mortality. Due to the slow progression of prostate cancer, such studies would require large cohorts with more than 15 years of follow-up. Finally, while the cohorts used in this study included patients of European descent, further studies are needed to investigate if our findings can be extended to other ethnic groups.","[{'e1': 'surgical margin status', 'e2': 'biochemical recurrence ', 'relation': ' was a significant predictor of ', 'condition': 'in uni- and multivariate Cox regression analysis in cohort 1'}]"
642,P89P22,"Our preliminary results indicate that kernel-based representations are highly effective for heterogeneous data fusion problems such as those considered in this work, as seen by the fact that a weighted multi-kernel data fusion method yielded the highest area under the ROC curve of over 0.8 in all three applications considered. Our results also suggest that in situations where the individual modalities demonstrate relatively poor discriminability, many of the data fusion methods may not yield accurate, discriminatory representations either. This implies that when developing such multimodal data fusion schemes, one must account for how noisy or sparse individual modality feature spaces are, as this could significantly affect embedding-based representations. Optimally weighting individual modalities or samples as implemented in the most successful data fusion strategy also appear to have a significant effect on the discriminability of the final integrated representation.","[{'e1': ' a weighted multi-kernel data fusion method', 'e2': 'the highest area under the ROC curve of over 0.8 ', 'relation': ' yielded ', 'condition': 'in all three applications considered'}]"
643,P90P1,"Background: Some studies have reported that deletions at chromosome arm 9p occur frequently and represent a critical step in carcinogenesis of some neoplasms. Our aim was to evaluate the deletion of locus 9p21 and chromosomes 3, 7 and 17 in localized prostate cancer and correlate these alterations with prognostic factors and biochemical recurrence after surgery.","[{'e1': ' deletions at chromosome arm 9p ', 'e2': 'a critical step ', 'relation': 'occur frequently and represent ', 'condition': 'in carcinogenesis of some neoplasms'}]"
644,P90P10,"Analyses of copy number alterations in prostate cancer have identified mutations associated with tumor development such as deletions of 1p, 6q, 8p and 9p and losses of large regions of chromosomes 13, 15 and 18. The locus 9p21 seems to be a critical region where losses have been correlated to worse prognoses in several cancers. Our group previously demonstrated that the loss of the 9p21 locus occurred in 15% of a sample of 94 clear cell carcinoma patients who underwent partial or radical nephrectomy. It was an independent predictor of specific mortality in multivariate analysis, and was associated with a 28-fold greater risk of death. Frequent allelic loss of 9p21 has also been reported in lung, ovarian, bladder, oral and head-and-neck cancers.","[{'e1': 'losses ', 'e2': 'worse prognoses ', 'relation': 'have been correlated to ', 'condition': 'in several cancers'}, {'e1': 'loss of the 9p21 locus ', 'e2': '15% of a sample of 94 clear cell carcinoma patients ', 'relation': 'occurred in ', 'condition': 'who underwent partial or radical nephrectomy'}]"
645,P90P12,"Contradictory to our findings, Visakorpi et al. evaluated 31 primary and 9 recurrent prostate cancer cases. Through comparative genomic hybridization analysis, they found that 74% of primary tumors showed DNA sequence copy number changes and that losses were 5 times more common than gains. Loss of 9p was observed in 16% of cases, and the other most common losses were 13q, 6q and 16q. Yet they found that recurrence was significantly associated only with gains on chromosome arm 8q and chromosomes X and 7. They concluded that losses of several chromosomal regions are common in primary tumors and suggested that deletional inactivation of putative tumor suppressor genes in these 3 chromosomal sites is likely to underlie prostate cancer development.","[{'e1': ' recurrence ', 'e2': 'gains ', 'relation': 'was significantly associated only with ', 'condition': 'on chromosome arm 8q and chromosomes X and 7'}]"
646,P90P13,"Corroborating our findings, Perinchery et al. mapped the 9p21 region in 40 primary tumors using 15 microsatellite markers and found that 72.5% of cases showed losses of heterozygosity on chromosome arm 9p. Only 6 of 15 microsatellite markers exhibited loss of heterozygosity in prostate cancer specimens, and the most common deletions were found on 9p21 at loci D9S1748, D9S171 and D9S270. There were also deletions on 9p22 at locus D9S162, on 9p13 at locus D9S273, and on 9p11 at locus D9S153. Deletions on 9p21 were associated with higher pathological stage; loss of heterozygosity at 3 or more loci occurred in 46% of stage T3 cases versus 15% of stage T2 cases, suggesting a higher incidence of loss of heterozygosity in the advanced stage of prostate cancer. They also demonstrated that the expression of p16 protein was either absent or very low, suggesting that the candidate target tumor suppressor gene at this locus was the gene that encodes protein p16.","[{'e1': ' 6 of 15 microsatellite markers ', 'e2': 'loss of heterozygosity ', 'relation': 'exhibited ', 'condition': 'in prostate cancer specimens'}, {'e1': ' the most common deletions ', 'e2': '9p21 ', 'relation': 'were found on ', 'condition': 'at loci D9S1748, D9S171 and D9S270'}]"
647,P90P16,"We acknowledge that our study is limited by its retrospective nature and that our conclusions require additional testing. However, based on our findings that 9p21 deletion was associated with worse outcome, we postulate that this deletion is a potential biomarker for prognosis in prostate cancer. Further prospective studies with larger series should be conducted to confirm our results and identify the gene at this locus. If these results are confirmed, they could be applied in clinical practice to improve the prognostic evaluation of patients with prostate cancer. In combination with other molecular and biochemical assays, tests for 9p21 deletions may help to identify patients with greater likelihood of prostate cancer recurrence so that they can be offered adjuvant treatment, and at the same time, this may spare many patients from unnecessary adjuvant therapies and their associated complications.","[{'e1': 'this deletion ', 'e2': 'prognosis ', 'relation': 'is a potential biomarker for ', 'condition': 'in prostate cancer'}]"
648,P90P17,"We found that deletions on chromosomes 3, 7 and 17 were rare events in our sample of localized prostate cancer cases. We also observed that locus 9p21 deletions were significantly correlated with shorter times to biochemical recurrence after surgery.","[{'e1': 'locus 9p21 deletions ', 'e2': 'shorter times to biochemical recurrence ', 'relation': 'were significantly correlated with ', 'condition': 'after surgery.'}]"
649,P90P3,"Radical prostatectomy is a treatment option for organ-confined tumors and demonstrates good results in large surgical series; however, up to a quarter of patients experience recurrence after surgery. Prior identification of patients with poor prognosis and higher chances of recurrence is important to determine cases requiring adjuvant treatments. The well-established classic prognostic parameters, such as Gleason score, stage and PSA, can estimate aggressiveness and recurrence in prostate cancer. However, these parameters are often deficient, even when used in combination, which may be due to the biological variability of prostate cancer.","[{'e1': 'Radical prostatectomy', 'e2': 'good results ', 'relation': ' demonstrates ', 'condition': 'in large surgical series'}, {'e1': 'a quarter of patients ', 'e2': 'recurrence', 'relation': 'experience ', 'condition': ' after surgery.'}, {'e1': 'prognostic parameters, such as Gleason score, stage and PSA', 'e2': 'aggressiveness and recurrence ', 'relation': 'can estimate ', 'condition': 'in prostate cancer'}]"
650,P90P4,"Conclusions: We found low rates of deletion in chromosomes 3, 7 and 17 and 9p21 locus. We observed that 9p21 locus deletion was associated with worse prognosis in localized prostate cancer treated by radical prostatectomy.","[{'e1': ' 9p21 locus deletion ', 'e2': 'worse prognosis in localized prostate cancer', 'relation': 'was associated with ', 'condition': ' treated by radical prostatectomy.'}]"
651,P90P5,"Loss of heterozygosity in a tumor suppressor locus is a common genetic alteration associated with malignancy, and the loss of various loci on chromosome 9 has been reported in various cancers. Global analyses of copy number profiles of primary tumors and metastases have identified recurrent aberrations associated with prostate cancer progression, such as broad deletions on the 1p, 6q, 8p and 9p chromosome arms and gains on the 1q, 3q, 7q and 8q genes. In vitro studies showed that the 9p21 and 7q22 loci are frequently deleted regions in prostate cancer cell lines. In agreement with this, loss of heterozygosity at the 9p21 locus was observed in 72% of 40 prostate cancer surgical specimens.","[{'e1': ' 9p21 and 7q22 loci ', 'e2': 'deleted regions ', 'relation': 'are frequently ', 'condition': 'in prostate cancer cell lines'}, {'e1': 'loss of heterozygosity ', 'e2': 'at the 9p21 locus', 'relation': ' was observed ', 'condition': 'in 72% of 40 prostate cancer surgical specimens.'}]"
652,P90P7,"This is the first study in the literature to demonstrate that the deletion of the 9p21 locus was independently associated with a shorter time to biochemical recurrence for localized prostate cancer following radical prostatectomy. We also demonstrated that deletions of chromosomes 3, 7 and 17 are extremely rare in localized tumors, and therefore have no role as potential biomarkers in prostate cancer. The strong points associated with our results were the extended postoperative follow-up, the fact that all patients underwent surgery by the same surgeon, and having cytogenetic alterations evaluated by the same uropathologist. The employment of a tissue microarray for expression analysis also facilitated homogeneity in our findings.","[{'e1': 'the deletion of the 9p21 locus ', 'e2': 'a shorter time to biochemical recurrence for localized prostate cancer ', 'relation': 'was independently associated with ', 'condition': 'following radical prostatectomy'}]"
653,P90P9,"The identification of loss of heterozygosity on specific genetic loci and other genetic changes has been helpful for understanding carcinogenesis, and has led to the description of new biomarkers and tools for prostate cancer. Recently the Oncotype Prostate DX was indicated as a test for counseling male patients with regard to the best course of therapy: active surveillance versus treatment. This tool is a quantitative RT-PCR assay performed on tissue obtained via needle biopsies, and incorporates 12 cancer-related genes that are algorithmically combined to calculate a Genomic Prostate Score, which correlates with the probability of harboring adverse pathologies at surgery.","[{'e1': 'Genomic Prostate Score ', 'e2': ' the probability of harboring adverse pathologies ', 'relation': 'correlates with', 'condition': 'at surgery.'}]"
654,P91P1,"Suppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic and micro-RNA-mediated repression of its gene expression in diverse cancers. In prostate cancer (PCa), elevated expression of miR-30d that targets SOCS1 mRNA is associated with increased risk of disease recurrence. SOCS1 can mediate its tumor suppressor functions by diverse mechanisms such as inhibiting the JAK-STAT signaling pathway, promoting the tumor suppressor functions of p53, attenuating MET receptor tyrosine kinase signaling and blocking the oncogenic potential of the cell cycle inhibitor p21CIP1 (p21). Here, we studied the expression of SOCS1 and the downstream targets of its putative tumor suppressor functions (p53, MET and p21) in human PCa specimens to evaluate their significance as markers of disease prognosis.","[{'e1': 'elevated expression of miR-30d that targets SOCS1 mRNA', 'e2': 'increased risk of disease recurrence', 'relation': ' is associated with ', 'condition': 'In prostate cancer (PCa)'}]"
655,P91P10,"We observed different staining intensities of SOCS1 in prostatectomy specimens that showed strong inverse correlation with the ISUP grade groups and Ki67 staining. Moreover, tumors with regional lymph node involvement showed significantly lower SOCS1 expression compared to those without. These findings indicate that SOCS1 expression is diminished during PCa progression and support the potential tumor suppressor role of SOCS1 in this cancer. Moreover, the finding that SOCS1 staining was reduced but not abolished in PCa specimens is consistent with the earlier reports that repression by CpG methylation occurs only in a small subset of PCa, whereas the expression of the SOCS1-targeting miR-30d is more frequent. Hence, evaluating SOCS1 protein would be more informative than quantifying CpG methylation of the SOCS1 gene, SOCS1-targeting micro-RNA or SOCS1 mRNA levels.","[{'e1': ' different staining intensities of SOCS1 ', 'e2': 'ISUP grade groups and Ki67 staining', 'relation': 'showed strong inverse correlation with the', 'condition': 'in prostatectomy specimens '}, {'e1': ' SOCS1 expression ', 'e2': ' potential tumor suppressor role of SOCS1 ', 'relation': 'supports the', 'condition': 'in this cancer'}]"
656,P91P14,"Tumors with regional lymph node metastasis, despite being limited in number, showed significantly lower SOCS1 and prostein expression and higher levels of Ki67, MET and p21 than those without lymph node involvement. SOCS1 might impinge on multiple signaling pathways that promote aggressive growth, migration, invasion and metastasis, resulting in metastatic spread to regional lymph nodes. Increased MET expression had been reported in metastatic PCa. We have recently shown using PCa cell lines that SOCS1 inhibits HGF-induced MET signaling and attenuated their migration and invasion. Consistent with this report, MET overexpression correlated with high proliferation and regional lymph node metastasis. However, we did not observe significant correlation between SOCS1 and MET protein expression. Several factors could contribute to this discrepancy between the studies on cell lines and in primary cancers. For instance, in primary cancers retaining SOCS1 expression, MET mutations might allow escape from SOCS1-mediated regulation. Alternatively, signaling pathways other than MET might contribute to aggressive growth of cancer cells retaining SOCS1 expression. The association between p21 and metastasis, but not with tumor grade is also intriguing. Although the number of metastatic cancers included in our study is small, our finding raises the possibility that the proposed function of cytosolic p21 in promoting cell motility might contribute to PCa metastasis. Even though the loss of SOCS1 did not correlate with increased MET or p21 expression as we had expected, our findings support the tumor suppressor function of SOCS1, and the oncogenic potential of MET and p21 in PCa. The expression of p21 also showed a strong correlation to AR levels, which is expressed in androgen-independent PCa and contributes to disease progression in a ligand-independent manner, renewing the interest in AR blockade. MET and AR levels also showed a marked tendency for positive correlation, although this was not statistically significant. Overall, the expression of SOCS1, MET and p21 in PCa specimens may be useful to identify cases that are prone to metastatic spread and thus to put them on more aggressive treatment and/or under close monitoring. While highly specific, clinical grade anti-p21 antibodies are available, anti-MET antibodies suitable for such use are still in development and efforts must be made to develop clinical grade SOCS1 antibodies.","[{'e1': ' MET mutations ', 'e2': 'escape from SOCS1-mediated regulation', 'relation': 'might allow ', 'condition': 'in primary cancers retaining SOCS1 expression'}, {'e1': 'cytosolic p21 ', 'e2': 'PCa metastasis', 'relation': 'might contribute to ', 'condition': 'in promoting cell motility'}, {'e1': 'AR levels ', 'e2': 'disease progression', 'relation': 'contributes to ', 'condition': ' in a ligand-independent manner'}]"
657,P91P6,"The suppressor of cytokine signaling 1 (SOCS1) protein is considered a tumor suppressor because of frequent repression of the SOCS1 gene promoter by CpG methylation in many types of cancers including hepatocellular carcinoma, leukemia and pancreatic adenocarcinoma. SOCS1 expression is also inhibited by microRNAs such as miR-19 and miR-155 in human cancers. SOCS1 is one of the genes that are under-expressed in the androgen-independent PCa cell line LNCaP-C81 compared to the androgen-dependent LNCaP-33 cell line. Even though methylation of the SOCS1 promoter occurs only in 20% of PCa cases, increased expression of the SOCS1-targeting micro-RNA, miR-30d, has been reported to occur frequently in PCa. In fact, elevated miR-30d expression in PCa specimens correlates with early biochemical recurrence, supporting a tumor suppressor role for SOCS1 in PCa. A number of studies have shown that SOCS1 attenuates growth of prostate cancer cells in vitro and in vivo.","[{'e1': 'elevated miR-30d expression ', 'e2': 'early biochemical recurrence', 'relation': 'correlates with ', 'condition': ' in PCa specimens'}, {'e1': 'SOCS1 ', 'e2': 'growth of prostate cancer cells ', 'relation': 'attenuates ', 'condition': 'in vitro and in vivo.'}]"
658,P91P7,"The SOCS1 gene is induced by diverse cytokines and growth factors, and inhibits their signaling in a negative feedback manner. SOCS1 has been shown to inhibit IL-6 and hepatocyte growth factor signaling, which are implicated in PCa pathogenesis. SOCS1 can exert its anti-tumor functions through diverse mechanisms. SOCS1 contains a central SH2 domain and C-terminal SOCS box. The SH2 domain binds to JAK kinases activated by cytokines and growth factor receptor tyrosine kinases, and thus blocks downstream signaling events. The SOCS box mediates ubiquitination of SOCS1-bound proteins, thereby promoting their degradation by proteasomes. We have shown that SOCS1 regulates HGF signaling by promoting ubiquitination and proteasomal degradation of the MET receptor tyrosine kinase. In cellular systems, SOCS1 co-operates with p53 to enforce oncogene-induced senescence. However, in a mouse model of hepatocellular carcinoma, SOCS1 deficiency is associated with increased expression of a p53 target gene, the cyclin-dependent kinase inhibitor p21CIP1/WAF1 (p21). Even though p21 generally functions as a tumor suppressor, its cytosolic localization may promote tumor growth. Indeed, overexpression of p21 occurs in several human cancers and correlates with poor prognosis. The relative contribution of the different downstream targets of SOCS1 in mediating tumor suppression in diverse cancers has not been studied yet. In PCa, even though p53 mutation is uncommon, MET and p21 are implicated in disease progression. Expression of MET occurs in 40% of localized PCa and correlates with Gleason score and lymph node metastasis, reaching nearly 100% in bone metastases. Similarly, increased expression of p21 mRNA and protein in PCa has been associated with progression to androgen-independent cancer and resistance to apoptosis induction by chemotherapeutic agents.","[{'e1': 'The SOCS1 gene ', 'e2': 'their signaling ', 'relation': 'inhibits ', 'condition': 'in a negative feedback manner'}, {'e1': 'SOCS1 ', 'e2': ' its anti-tumor functions ', 'relation': 'can exert', 'condition': 'through diverse mechanisms'}, {'e1': 'SOCS1 ', 'e2': 'HGF signaling ', 'relation': 'regulates ', 'condition': 'by promoting ubiquitination and proteasomal degradation of the MET receptor tyrosine kinase'}, {'e1': ' SOCS1', 'e2': 'p53 to enforce oncogene-induced senescence', 'relation': ' co-operates with ', 'condition': 'In cellular systems'}, {'e1': ' SOCS1 deficiency ', 'e2': 'increased expression of a p53 target gene', 'relation': 'is associated with ', 'condition': 'in a mouse model of hepatocellular carcinoma'}, {'e1': ' SOCS1 deficiency ', 'e2': 'the cyclin-dependent kinase inhibitor p21CIP1/WAF1 (p21)', 'relation': 'is associated with ', 'condition': 'in a mouse model of hepatocellular carcinoma'}, {'e1': 'increased expression of p21 mRNA and protein ', 'e2': ' progression to androgen-independent cancer ', 'relation': 'has been associated with', 'condition': 'in PCa'}, {'e1': 'increased expression of p21 mRNA and protein ', 'e2': 'resistance to apoptosis induction by chemotherapeutic agents.', 'relation': 'has been associated with', 'condition': 'in PCa'}]"
659,P93P1,"The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions but unrelated to deletions of 3p, 5q and 6q. In univariate analysis, high ADAM15 expression was strongly linked to PSA recurrence. However, in multivariate analyses this association was only maintained if the analysis was limited to preoperatively available parameters in ERG-negative cancers. The results of our study demonstrate that ADAM15 is strongly up regulated in a small but highly aggressive fraction of prostate cancers. In these tumors, ADAM15 may represent a suitable drug target. In a preoperative scenario, ADAM15 expression measurement may assist prognosis assessment, either alone or in combination with other markers.","[{'e1': ' negative ADAM15 staining', 'e2': '87.7% of 9826 interpretable tumors', 'relation': ' was found in ', 'condition': ' In prostate cancers'}, {'e1': 'weak ADAM15 staining', 'e2': '3.7% of 9826 interpretable tumors', 'relation': ' was found in ', 'condition': ' In prostate cancers'}, {'e1': 'moderate ADAM15 staining', 'e2': '5.6% of 9826 interpretable tumors', 'relation': ' was found in ', 'condition': ' In prostate cancers'}, {'e1': 'strong ADAM15 staining', 'e2': '3.0% of 9826 interpretable tumors', 'relation': ' was found in ', 'condition': ' In prostate cancers'}, {'e1': ' high ADAM15 expression ', 'e2': 'PSA recurrence', 'relation': 'was strongly linked to ', 'condition': 'In univariate analysis'}]"
660,P93P3,"The human A Disintegrin and Metalloproteinase 15 (ADAM15) is one of more than 20 members of the ADAM family of type I multi-domain transmembrane glycoproteins that function as zinc-dependent endopeptidases. Activated ADAM15 is involved in proteolytic processing of cytokines, growth factors and adhesions molecules. ADAM15 promotes cancer progression in gastric, lung and colon cancers as well as melanomas. It is believed that the tumor promoting action of ADAM15 results from disruption of cell–cell and cell-matrix adhesion and from release of membrane-bound growth factors. Accordingly, ADAM15 deregulation has been linked to poor patient outcome in lung and colon cancers.","[{'e1': 'ADAM15', 'e2': 'cancer progression', 'relation': ' promotes ', 'condition': ' in gastric cancer'}, {'e1': 'ADAM15', 'e2': 'cancer progression', 'relation': ' promotes ', 'condition': 'in lung cancer'}, {'e1': 'ADAM15', 'e2': 'cancer progression', 'relation': ' promotes ', 'condition': 'in colon cancer'}, {'e1': 'ADAM15', 'e2': 'cancer progression', 'relation': ' promotes ', 'condition': 'in melanomas'}, {'e1': 'ADAM15 deregulation ', 'e2': 'poor patient outcome ', 'relation': 'has been linked to ', 'condition': 'in lung cancers '}, {'e1': 'ADAM15 deregulation ', 'e2': 'poor patient outcome ', 'relation': 'has been linked to ', 'condition': 'in colon cancers.'}]"
661,P93P7,"Our immunohistochemical analysis revealed membranous ADAM15 staining of variable intensity, typically located at the apical cell pole, in a small fraction of our 9826 analyzable prostate cancers, while normal prostate epithelium and other non-malignant cells were negative under the selected experimental conditions. Absence of ADAM15 expression in normal prostatic epithelium was also described in one earlier study. High-level ADAM15 staining was strongly linked to adverse phenotypical features of prostate cancer and early PSA recurrence in our study. Similar findings were made by Kuefer et al. using a different scoring scheme that does not disclose the fraction of positive cancer samples. That a statistical association was not found in this study might be due to a relatively low number of cases. Overall, these findings from our study provide strong in vivo evidence for a role of ADAM15 expression in development and progression of prostate cancer. This assumption is strongly supported by earlier in vivo evidence from functional studies using prostate cancer cell lines. These data had suggested that ADAM15 overexpression contributes to the metastatic cascade by prostate tumor cell interaction with vascular endothelium and thus facilitating blood vessel invasion.","[{'e1': ' High-level ADAM15 staining ', 'e2': 'adverse phenotypical features of prostate cancer and early PSA recurrence ', 'relation': 'was strongly linked to ', 'condition': 'in our study'}, {'e1': 'ADAM15 overexpression ', 'e2': 'the metastatic cascade ', 'relation': 'contributes to ', 'condition': 'by prostate tumor cell interaction with vascular endothelium and thus facilitating blood vessel invasion.'}]"
662,P93P8,"The large number of cancers included in our study enabled us to investigate possible associations of ADAM15 expression with previously established molecular key features of prostate cancer. Our data demonstrate a strong link of ADAM15 expression to ERG activation. In about 50% of tumors, fusion of the androgen receptor-regulated TMPRSS2 gene with ERG leads to AR-stimulated overexpression of ERG, an ETS-transcription factor. ERG is a pioneering factor that modulates transcription of more than 1600 genes, including many AR regulated genes as it opens cryptic AR binding sites in the vicinity of its own recognition site when bound to gene promoters. Cell line models suggesting AR-dependent ADAM15 expression provide a possible mechanistic explanation for the strong association between ADAM15 expression and ERG fusion, which was also observed by others.","[{'e1': ' fusion of the androgen receptor-regulated TMPRSS2 gene with ERG ', 'e2': 'AR-stimulated overexpression of ERG', 'relation': 'leads to ', 'condition': ' In about 50% of tumors'}]"
663,P94P1,"Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD.","[{'e1': 'overexpression of the AR NTD ', 'e2': 'the growth of prostate cancer ', 'relation': 'inhibited ', 'condition': 'in castrated hosts'}, {'e1': 'overexpression of the AR NTD ', 'e2': 'the progression of prostate cancer ', 'relation': 'inhibited ', 'condition': 'in castrated hosts'}, {'e1': 'lentivirus delivery of decoys ', 'e2': ' hormonal progression ', 'relation': 'delayed', 'condition': 'in castrated hosts'}]"
664,P94P3,"In 2007, the first in vivo proof-of-concept for AR NTD as a novel therapeutic target was provided using copies (decoys) of the AR NTD residues 1–558 (AR1-558). In non-castrated hosts, these decoys reduced tumor incidence, decreased tumor growth and serum PSA levels. Here we provide evidence that lentiviral delivery of decoys to mice bearing established prostate cancer xenografts inhibited hormonal progression to castration-recurrence as well as investigated possible mechanisms through which decoys exert their activity.","[{'e1': 'these decoys ', 'e2': 'tumor incidence', 'relation': 'reduced ', 'condition': ' In non-castrated hosts'}, {'e1': 'these decoys ', 'e2': 'tumor growth and serum PSA levels', 'relation': 'decreased ', 'condition': ' In non-castrated hosts'}]"
665,P94P4,"Androgen deprivation therapy causes a temporary reduction in tumor burden concomitant with a decrease in serum levels of PSA which is an AR-regulated gene. Unfortunately, prostate cancer will eventually begin to grow again in the absence of androgens to form castration-recurrent disease as characterized by a rising titer of serum PSA. Enzalutamide and abiraterone initially reduce serum PSA and increase survival by approximately 6 months in castration-recurrent patients. Resistance to these drugs is associated with increasing serum levels of PSA which implies re-activation of AR transcriptional activity.","[{'e1': 'Enzalutamide and abiraterone ', 'e2': 'serum PSA ', 'relation': 'reduces ', 'condition': ' in castration-recurrent patients'}, {'e1': 'Enzalutamide and abiraterone ', 'e2': 'survival by approximately 6 months,', 'relation': 'increases', 'condition': ' in castration-recurrent patients'}]"
666,P94P5,"Evidence supporting the in vivo efficacy of targeting the AR NTD was shown by application of decoy AR1-558 molecules of AR NTD that inhibit the growth and hormonal progression of prostate cancer xenografts both in the presence and absence of androgen. Those studies applied two models: one model used cells that stably expressed decoy AR1-558 to grow tumors with decoy; and the other model applied lentivirus delivery of decoy to established tumors in non-castrated mice. Here we investigated the effects of decoy in established tumors combined with castration. This is a model that better reflects the clinical representation of patients that undergo androgen deprivation therapy and develop castration-recurrent disease. Non-transfected LNCaP tumors were first established in NOD-SCID mice prior to castration and lentivirus delivery of the decoys. PSA nadir, time for PSA to reach pre-castration levels, and the time for the tumor to double in volume after therapy were all measured as an indication of tumor progression as reported in clinical studies. Patients have a better prognosis when their PSA nadir reaches very low levels, or with long periods of the time required for rises in PSA or for their tumor volume to double. Our studies showed that the delivery of decoys to established tumors leads to a lower nadir, increased time for the tumor to double in volume as well as for PSA to reach the pre-castrate levels. These data concur with delayed hormonal progression in xenografts of LNCaP cells stably expressing decoy in castrated mice and suggests that tumor progression is at least in part dependent on the AR NTD.","[{'e1': 'decoy AR1-558 molecules of AR NTD ', 'e2': 'the growth and hormonal progression of prostate cancer xenografts ', 'relation': 'inhibit', 'condition': 'in the presence of androgen'}, {'e1': 'decoy AR1-558 molecules of AR NTD ', 'e2': 'the growth and hormonal progression of prostate cancer xenografts ', 'relation': 'inhibit', 'condition': 'in the absence of androgen'}]"
667,P95P10,"Last, our results corroborate the findings reported by prior work, which suggested that adjuvant radiation therapy may offer significantly greater clinical recurrence-free survival than salvage radiation therapy in men with high Decipher score, but not in men with lower Decipher scores. Nonetheless, there are key differences as well. Most importantly, the control group in that study excluded men treated with initial observation. Given that 35% to 40% of patients treated with initial observation may not experience a biochemical recurrence within 10 years of radical prostatectomy, thereby obviating the need for salvage therapy, inclusion of such patients is necessary in deriving conclusions regarding the oncologic efficacy of adjuvant radiation therapy. The median time to salvage radiation therapy was 11.1 months in our cohort, compared with 5 months in the prior study, more closely reflecting the natural history of an initial observation versus an upfront adjuvant radiation therapy approach in the post-radical-prostatectomy setting. Next, the concordance index of the Decipher-only model in our study was somewhat lower compared with that reported previously. As alluded to earlier, this could be due to different patient populations in the initial observation arm, with or without salvage radiation therapy, and although direct comparison of adjuvant radiation therapy with only salvage radiation therapy may improve the discrimination power from a statistical standpoint, it may not be truly reflective of a clinical setting. Finally, risk stratification of patients into those likely to benefit from upfront adjuvant radiation therapy versus those who may not was based solely on low versus intermediate/high Decipher score in the prior study. We have previously shown the prognostic role of histopathologic features, such as pathologic stage, Gleason score, and presence of lymph node invasion, in predicting cancer-specific mortality in patients undergoing adjuvant radiation therapy. As such, our current study shows that incorporating both Decipher and clinicopathologic features results in better accuracy when predicting clinical recurrence after surgery.","[{'e1': ' adjuvant radiation therapy ', 'e2': 'significantly greater clinical recurrence-free survival than salvage radiation therapy ', 'relation': 'may offer ', 'condition': 'in men with high Decipher score'}, {'e1': 'incorporating both Decipher and clinicopathologic features ', 'e2': 'better accuracy ', 'relation': 'results in ', 'condition': 'when predicting clinical recurrence after surgery.'}]"
668,P95P3,"Overall, 21.9% of patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year clinical recurrence rate was 4.9% versus 17.4% in patients treated with aRT versus initial observation. Pathologic T3b/T4 stage, Gleason score 8–10, lymph node invasion, and Decipher score greater than 0.6 were independent predictors of clinical recurrence. The cumulative number of risk factors was 0, 1, 2, and 3 to 4 in 46.5%, 28.9%, 17.2%, and 7.4% of patients, respectively. aRT was associated with decreased clinical recurrence rate in patients with two or more risk factors, with a 10-year clinical recurrence rate of 10.1% with aRT versus 42.1% with initial observation, but not in those with fewer than two risk factors.","[{'e1': 'aRT ', 'e2': 'decreased clinical recurrence rate ', 'relation': 'was associated with ', 'condition': 'in patients with two or more risk factors'}]"
669,P95P8,"Our analyses showed several important findings. First, we demonstrate that incorporating Decipher added incremental prognostic value in identifying patients with adverse pathologic features, such as extraprostatic disease, pathologic Gleason score 8 to 10, or presence of lymph node invasion, at a higher risk of clinical recurrence after radical prostatectomy, with a predictive accuracy of 85%. Based on the combined clinicopathologic and genomic parameters, we created a novel nomogram to quantify the likelihood of clinical recurrence-free survival 5 and 10 years after radical prostatectomy, stratified by receipt of adjuvant radiation therapy, which showed optimal discrimination and calibration characteristics. Whereas prior studies have combined Decipher with pre-existing validated models such as the postsurgical Cancer of the Prostate Risk Assessment or the Stephenson nomogram, our study attempted to incorporate genomic features with routinely available clinicopathologic parameters to create a de novo prediction model. This was then used to derive an easily used risk score. Importantly, every one-point increment in the risk score was associated with a doubling of clinical recurrence risk at 10 years after radical prostatectomy. This study is based on genomic parameters that adhere to the recently published TRIPOD guidelines for developing and reporting prognostic models. Adherence to the guidelines increases the methodological strengths of the study and allows readers to transparently assess the risk of bias and potential usefulness in a given clinical setting. Our work represents a type 1b study per the TRIPOD statement, corresponding to development and internal validation, and lays the foundation for future external validation studies.","[{'e1': 'every one-point increment in the risk score ', 'e2': 'a doubling of clinical recurrence risk at 10 years ', 'relation': 'was associated with ', 'condition': 'after radical prostatectomy'}]"
670,P96P11,"As the number of large-scale genomics datasets exponentially increases due to decreasing experimental costs, current limitations reside in our capacity to extract relevant information. Our study illustrates a novel pipeline applicable to any range of disease cohorts that can assist in mining these datasets in a robust and unbiased way to generate clinically relevant knowledge. Combinatorial enumeration of all possible subsets of n genes with disease-free survival helps isolate k gene sets based on statistical significance. From there, we are able to identify an optimal gene set signature, whose dysregulation can be associated with disease-free survival in early stage prostate cancer patients. We illustrate this process with ALDH1A2, where by using this retinoic acid pathway gene as a seed for the data-mining pipeline, we identify an initial set of 11 genes, which is reduced by statistical significance, first to 2 gene sets, and then refined to an optimal gene set containing just two genes. This optimal gene signature has significant predictive power of relapse, both alone and in combination with the traditional histological Gleason score.","[{'e1': 'an optimal gene set signature, whose dysregulation ', 'e2': 'disease-free survival ', 'relation': 'can be associated with ', 'condition': 'in early stage prostate cancer patients'}]"
671,P96P13,"We investigated the relationship between disease-free survival and every possible candidate gene set based on the core gene set, defined as the power set of the core gene set. The Kaplan–Meier log-rank statistic was used for unbiased exploration of these gene subsets in correlation with disease-free survival, producing a disease-free survival landscape. Surprisingly, the Kaplan–Meier p-values were found to be statistically significant for only two gene sets, at a probability of 2/2047 = 0.1%. The optimal gene set comprises CYP26C1 and RDH10, both of which coordinate tightly with ALDH1A2 to control retinoic acid activities. We then compared disease-free survival in the patient cohort with altered expression of the two genes in the optimal gene set. Being positive for the optimal gene set, defined as having significantly altered expression of any or all of the genes in the optimal gene set signature, was associated with statistically significant poor survival. A strong correlation is seen between the optimal gene set and disease-free survival: patients with the optimal gene set have median disease-free survival of 62.7 months while more than 55% patients without the optimal gene set are still disease-free after 150 months.","[{'e1': 'the Kaplan–Meier p-values ', 'e2': 'statistically significant ', 'relation': 'were found to be ', 'condition': 'for only two gene sets, at a probability of 2/2047 = 0.1%'}]"
672,P96P14,"The decision to use ALDH1A2 as a seed for our case study comes from the increasing evidence for the role of retinoic acids in mammalian homeostasis and disease, especially the intimate association of the retinoic acid signaling pathway with a variety of cancers, including leukemia, neuroblastomas, and carcinomas, as well as gastric, ovarian, lung, breast, colon, rectal, pancreatic, and prostate cancers. In prostate cancer, a previous study has found hypermethylation of ALDH1A2 in cancer cell lines subjected to treatment with the chemotherapeutic agent 5-aza-2′-deoxycytidine. Hypermethylation of ALDH1A2 led to reduced gene expression in prostate cancer cell lines. Moreover, ALDH1A2 levels were also reduced in human primary prostate tumors when compared with normal prostate tissue. Reduced expression of ALDH1A2 also correlated with shorter recurrence-free survival of patients, suggesting that ALDH1A2 may in fact be a tumor suppressor gene for prostate cancer. A second study using an adenocarcinoma prostate model confirmed reduction of ALDH1A2 in prostate tumors in mice. This study was further supported by measuring ALDH1A2 protein levels in prostate tissue from prostate cancer patients, where prostate cancer tissue samples showed reduced ALDH1A2 expression compared with healthy tissue. Finally, the ALDH1A2 case study has been chosen because of its potential significance in other disease models, as we have previously demonstrated that the ALDH1A2 pathway is involved in a completely different disease context, i.e., cardiac fibrosis.","[{'e1': 'Hypermethylation of ALDH1A2 ', 'e2': 'reduced gene expression ', 'relation': 'led to ', 'condition': 'in prostate cancer cell lines'}]"
673,P96P3,"As a case study, we applied this pipeline to systematically analyze the role of ALDH1A2 in prostate cancer. We have previously found this gene to have multiple roles in disease and homeostasis, and here we investigate the role of the associated ALDH1A2 gene/protein networks in prostate cancer, using our methodology in combination with prostate cancer patient clinical profiles from ICGC and TCGA databases. Relationships between gene signatures and relapse were analyzed using Kaplan–Meier log-rank analysis and multivariable Cox regression. Relative expression versus pooled mean from diploid population was used for z-statistics calculation. Gene/protein interaction network analyses generated 11 core genes associated with ALDH1A2; combinatorial ranking of the power set of these core genes identified two gene sets with significant correlation with disease relapse. For the more significant of these two sets, referred to as the optimal gene set, patients have median survival 62.7 months with optimal gene set alterations compared to more than 150 months without optimal gene set alterations. Two genes comprising the optimal gene set (CYP26A1 and RDH10) are strongly associated with ALDH1A2 in the retinoic acid pathways, suggesting a major role of retinoic acid signaling in early prostate cancer progression. Our pipeline complements human expertise in the search for prognostic biomarkers in large-scale datasets.","[{'e1': ' CYP26A1 and RDH10 ', 'e2': 'ALDH1A2 ', 'relation': 'are strongly associated with ', 'condition': 'in the retinoic acid pathways'}, {'e1': 'Our pipeline ', 'e2': 'human expertise ', 'relation': 'complements ', 'condition': 'in the search for prognostic biomarkers in large-scale datasets.'}]"
674,P97P8,"The interest for active surveillance is increasing in very-low and low risk disease. The prediction of pathological stage of the disease plays an important role to guide treatment decisions in low risk PCa, an example is the recent study in which candidates for active surveillance had a good oncological outcome despite upstaging on final pathological stage. Competing risks also pose a very delicate issue: life expectancy, biochemical recurrence and cancer-specific mortality need to be predicted with distant end-points, while most studies are limited to 5-year follow-up, which is inadequate for quality planning. Biochemical recurrence is crucial in deciding whether adjuvant therapy is needed: the 20-year follow-up Suardi nomogram proved to be accurate, and more recently proportion of Gleason score 4 in index lesion has been shown to be a simple and reliable predictor of biochemical recurrence. While the final benchmark for effectiveness of a tool is the clinical consequences, the quality of a nomogram should be evaluated by its accuracy. Cancer specific mortality is the most important single endpoint in PCa: CAPRA-s has been validated as a well performing tool, and when integrated with genomic classifiers helps identifying patients with significantly elevated risk for lethal PCa. Risk of metastatic progression has been assessed accurately by the CAPRA-s, and recently, the CCP genomic classifier was validated as outperforming the CAPRA-s in prediction of aggressiveness and metastatic progression risk.","[{'e1': 'the CCP genomic classifier ', 'e2': ' the CAPRA-s ', 'relation': 'was validated as outperforming', 'condition': 'in prediction of aggressiveness and metastatic progression risk.'}]"
675,P98P5,"We measured the DNA-PK activity of peripheral blood lymphocytes because it is not productive to evaluate the DNA-PK activity of infinitesimally small tumor biopsy tissue specimens. Auckley et al. demonstrated a tight correlation between the DNA-PK activity in PBLs and that in bronchial epithelial cells that had been obtained by bronchoscopy, suggesting that PBLs can be used as a surrogate cell type for other kinds of cells. Using PBLs, we have performed several studies seeking to predict prognosis after radiotherapy. We showed that the level of DNA-PK activity in PBLs might be a prognostic indicator for the response of several types of advanced cancer to radiotherapy. In breast cancer patients, the level of DNA-PK activity in PBLs was related to tumor aggressiveness and to the presence of axillary lymph node metastasis.","[{'e1': ' the level of DNA-PK activity in PBLs', 'e2': 'tumor aggressiveness ', 'relation': ' was related to ', 'condition': 'In breast cancer patients'}, {'e1': ' the level of DNA-PK activity in PBLs', 'e2': ' the presence of axillary lymph node metastasis.', 'relation': ' was related to ', 'condition': 'In breast cancer patients'}]"
676,P98P7,"The present study demonstrated that after radiotherapy for localized prostate cancer, patients with low PBL DNA-PK activity had a significantly higher PSA relapse rate than patients with high PBL DNA-PK activity. We previously reported that among patients with breast cancer, uterine cervical cancer and head-and-neck cancer, low PBL DNA-PK activity was associated with a higher incidence of distant metastasis and a worse prognosis than high PBL DNA-PK activity. Therefore, low DNA-PK activity in PBLs may be a potential marker of a worse prognosis for breast cancer, cervical cancer and head-and-neck cancer due to the associated higher frequency of distant metastasis. In the current study, only one of 69 patients with PSA relapse had distant metastasis and regional lymph node metastasis, indicating that PSA relapse was overwhelmingly due to local failure. The detailed reasons for why low PBL DNA-PK activity was associated with radioresistance of prostate cancer are not very well understood. The relationship between PBL DNA-PK activity and the NCCN risk group indicated that DNA-PK activity tended to decrease as the NCCN risk increased. Since the NCCN risk is an important prognostic factor for patients receiving radiotherapy, patients with low PBL DNA-PK activity could have had a worse prognosis due to their more advanced NCCN risk. Lower level of DNA-PK activity could profoundly affect DNA DSB repair, resulting in the perpetuation of chromosomal damage. We have previously demonstrated that low DNA-PK activity is related to chromosomal instability. Aggressive features of cancer, such as a higher NCCN risk classification, result from many different genetic alterations that promote rapid tumor cell proliferation and metastasis. Genetic instability can lead to loss or activation of a number of critical genes involved in cell proliferation, differentiation, and apoptosis. Low PBL DNA-PK activity might be associated with phenotypic features of tumor aggressiveness, such as a higher risk of PSA relapse of prostate cancer.","[{'e1': 'patients with low PBL DNA-PK activity', 'e2': 'PSA relapse rate than patients with high PBL DNA-PK activity.', 'relation': ' had a significantly higher ', 'condition': 'after radiotherapy for localized prostate cancer'}, {'e1': ' low PBL DNA-PK activity ', 'e2': 'a higher incidence of distant metastasis ', 'relation': 'was associated with ', 'condition': 'among patients with breast cancer'}, {'e1': ' low PBL DNA-PK activity ', 'e2': 'a higher incidence of distant metastasis ', 'relation': 'was associated with ', 'condition': 'among patients with uterine cervical cancer'}, {'e1': ' low PBL DNA-PK activity ', 'e2': 'a higher incidence of distant metastasis ', 'relation': 'was associated with ', 'condition': 'among patients with head-and-neck cancer'}, {'e1': ' low PBL DNA-PK activity ', 'e2': 'a worse prognosis than high PBL DNA-PK activity', 'relation': 'was associated with ', 'condition': 'among patients with breast cancer'}, {'e1': ' low PBL DNA-PK activity ', 'e2': 'a worse prognosis than high PBL DNA-PK activity', 'relation': 'was associated with ', 'condition': 'among patients with uterine cervical cancer'}, {'e1': ' low PBL DNA-PK activity ', 'e2': 'a worse prognosis than high PBL DNA-PK activity', 'relation': 'was associated with ', 'condition': 'among patients with head-and-neck cancer'}]"
677,P98P8,"We found a borderline relationship between PBL DNA-PK activity and urinary toxicity. That is, the low PBL DNA-PK activity group tended to have a higher incidence of Grade 1–2 urinary toxicity than the high PBL DNA-PK activity group. In contrast, there was no relationship between PBL DNA-PK activity and rectal toxicity. We previously reported that Grade 2–3 rectal bleeding after radiotherapy for prostate cancer was well correlated with the combination of low Ku80 expression and radiation-induced miR-99a expression in PBLs. The miR-99 family of miRNAs targets SWI/SNF chromatin remodeling factor SNF2H/SMARCA5. Remodeling of chromatin seems to be crucial during the early stages of the NHEJ pathway to facilitate chromatin relaxation and allow repair proteins to access the sites of DNA DSBs. Introduction of the miR-99 family of miRNAs into cells reduces the rate and overall efficiency of repair by both HR and NHEJ. Taken together, these results indicate that both urinary and rectal toxicity of radiotherapy for prostate cancer are related to the repair capacity for DNA DSBs, suggesting that measurement of the activity or expression of proteins involved with NHEJ could be a promising approach to the prediction of urinary toxicity and rectal toxicity.","[{'e1': ' Grade 2–3 rectal bleeding ', 'e2': 'the combination of low Ku80 expression and radiation-induced miR-99a expression ', 'relation': 'was well correlated with ', 'condition': 'after radiotherapy for prostate cancer'}, {'e1': ' Grade 2–3 rectal bleeding ', 'e2': 'the combination of low Ku80 expression and radiation-induced miR-99a expression ', 'relation': 'was well correlated with ', 'condition': 'in PBLs'}]"
678,P99P14,"In a large multicenter sample of men with adverse pathologic features with the longest follow-up to date, the Decipher genomic classifier demonstrated a potentially clinically important improvement in prediction of prostate cancer-specific mortality at 10 years in all men, as well as in subgroups considered high risk based on prostate-specific antigen, stage, or Gleason score, and very high risk men who experienced early biochemical recurrence, or who developed metastasis after radical prostatectomy. Adding the genomic classifier to a model with either CAPRA-S or individual clinical variables improved prediction of prostate cancer-specific mortality within 10 years, and identified subgroups of men with very low risk of prostate cancer-specific mortality at 10 years who may be suitable for conservative postsurgical management, and men with very high risk who may require more aggressive therapy. Clinical trials are needed to determine whether the combination of the Decipher genomic classifier and CAPRA-S can improve treatment assignment and outcomes compared to clinical variables alone.","[{'e1': 'the Decipher genomic classifier ', 'e2': 'potentially clinically important improvement ', 'relation': 'demonstrated a ', 'condition': 'in prediction of prostate cancer-specific mortality at 10 years in all men'}, {'e1': 'the Decipher genomic classifier ', 'e2': 'potentially clinically important improvement ', 'relation': 'demonstrated a ', 'condition': ' in subgroups considered high risk based on prostate-specific antigen'}, {'e1': 'very high risk men ', 'e2': 'early biochemical recurrence', 'relation': 'experienced ', 'condition': 'after radical prostatectomy'}, {'e1': 'very high risk men ', 'e2': 'metastasis', 'relation': 'developed ', 'condition': 'after radical prostatectomy'}]"
679,P99P15,"In men with adverse pathology or early disease progression after prostatectomy, the Decipher 22 gene genomic classifier predicts risk of prostate cancer death. When combined with the Cancer of the Prostate Risk Assessment Postsurgical Score it further stratifies risk, which may be useful for decisions about postprostatectomy treatment.","[{'e1': 'the Decipher 22 gene genomic classifier ', 'e2': ' risk of prostate cancer death', 'relation': 'predicts', 'condition': 'In men with adverse pathology '}, {'e1': 'the Decipher 22 gene genomic classifier ', 'e2': ' risk of prostate cancer death', 'relation': 'predicts', 'condition': 'in men with early disease progression after prostatectomy'}]"
680,P99P8,"Currently, surgical pathology features are the primary means to identify men at highest risk of prostate cancer-specific mortality. Despite the ability of these features to stratify PCSM risk, there remains considerable variability in outcomes when applied to individual men with prostate cancer. To improve prognostic accuracy and clinical decision-making, several risk classifiers have been developed based on biomarker signatures alone or integrated with clinical features. One of the signatures most extensively tested and validated for predicting risk of metastasis in men at intermediate and high risk is the Decipher genomic classifier, comprised of 22 gene expression markers derived from whole transcriptomic analysis of formalin fixed paraffin embedded tissue. The genomic classifier generates a score from 0 to 1, with higher values associated with worse outcomes. Recently the genomic classifier was also shown to predict risk of prostate cancer-specific mortality in men with high risk based on preoperative prostate-specific antigen levels or pathology.","[{'e1': 'the genomic classifier', 'e2': 'risk of prostate cancer-specific mortality', 'relation': ' was also shown to predict ', 'condition': ' in men with high risk based on preoperative prostate-specific antigen levels or pathology.'}]"