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EZH2 | Enhancer of Zeste Homolog 2 |
DACT3 | Disheveled-binding Antagonist of β-catenin 3 |
H3K4me3 | Histone 3 lysine 4 trimethylation |
Suz12 | Suppressor of Zeste 12 |
SirT1 | Sirtuin 1 |
BMI1 | B lymphoma Mo-MLV insertion region 1 homolog |
Lef1 | Lymphoid Enhancer-binding Factor 1 |
Slug | Snail family transcriptional repressor 2 |
ZEB1 | Zinc Finger E-box-binding Homeobox 1 |
Snail | Snail family transcriptional repressor 1 |
ZEB2 | Zinc Finger E-box-binding Homeobox 2 |
FOXC2 | Forkhead Box C2 |
TWIST2 | Twist family bHLH transcription factor 2 |
CD44 | Cluster of Differentiation 44 |
CD133 | Cluster of Differentiation 133 |
SIP1 | Smad Interacting Protein 1 |
BMP-6 | Bone Morphogenetic Protein 6 |
ECM | extracellular matrix |
TME | tumor microenvironment |
α-SMA | alpha-smooth muscle actin |
CAFs | cancer-associated fibroblasts |
HGF | hepatocyte growth factor |
MET receptor | Mesenchymal–Epithelial Transition receptor |
MCF10 | original non-tumorigenic human mammary epithelial cell line |
HGF/MET | Hepatocyte Growth Factor/MET receptor signaling pathway |
HFD | high-fat diet |
CEACAM1 | in carcinoembryonic antigen-related cell adhesion molecule 1 |
MVD | Microvessel Density |
PKC-α | Protein Kinase C alpha |
MEK3 | Mitogen-activated protein kinase kinase 3 |
AMPKα | AMP-activated protein kinase alpha subunit |
TILs | tumor-infiltrating lymphocytes |
Foxp3 | Forkhead box P3 |
Tregs | regulatory T cells |
S100A9 | S100 calcium-binding protein A9 |
PMN | polymorphonuclear neutrophils |
Ly6G+ | Lymphocyte antigen 6 complex, locus G positive |
HIF 1α | 1hypoxia-inducible factor-1α |
VEGF | vascular endothelial growth factor |
DCE-MRI | Dynamic contrast-enhanced MRI |
sEVs | small extracellular vesicles |
PMN-MDSCs | polymorphonuclear myeloid-derived suppressor cells |
IGF | Insulin-like growth factor |
MAPK | Mitogen-Activated Protein Kinase |
ET | Endocrine Therapy |
ROS | reactive oxygen species |
GPER | G protein-coupled estrogen receptor |
EDCs | Endocrine-disrupting chemicals |
BPA | Bisphenol A |
DDT | Dichlorodiphenyltrichloroethane |
CYP19A1 | Cytochrome P450 Family 19 Subfamily A Member 1 |
PM | particulate matter |
PAHs | polycyclic aromatic hydrocarbons |
## Author Contributions |
Conceptualization, A.S.Ș. and M.M.O.; methodology, B.-A.G.; software, T.C.P.; validation, A.S.Ș., B.-A.G. and L.P.M.; formal analysis, R.T.S.; investigation, A.B.B., E.D.; resources, A.M.-C.; data curation, M.E.J.; writing—original draft preparation, A.S.Ș.; writing—review and editing, C.C.; visualization, L.P.M.; supe... |
## Data Availability Statement |
No new data were created or analyzed in this study. Data sharing is not applicable to this article. |
## Conflicts of Interest |
The authors declare no conflicts of interest. |
## Funding Statement |
This research received no external funding. |
## Footnotes |
## References |
## Associated Data |
### Data Availability Statement |
No new data were created or analyzed in this study. Data sharing is not applicable to this article. |
929b77676fd37e98668acaa70e01667a61eae5f53f33d17fbbb4ee393a0a30cb pmc12937821.txt |
PMCID: PMC13042621 |
TITLE: Isocitrate Dehydrogenase‐Mutant Astrocytomas: Risk Stratification and Therapeutic Advance |
LICENSE: https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
ABSTRACT: ABSTRACTIsocitrate dehydrogenase (IDH)–mutant astrocytomas are recognized as a single molecular entity spanning CNS WHO Grades 2–4, and clinical behavior is shaped by early lineage‐defining alterations (IDH1/2, ATRX, TP53) and by later events linked to malignant transformation (e.g., CDKN2A/B homozygous delet... |
## Introduction |
Diffuse astrocytomas represent a major subset of infiltrative primary brain tumors in adults, characterized by biological heterogeneity, diffuse invasion, and an ultimately incurable course despite often prolonged survival [1, 2]. The discovery of recurrent isocitrate dehydrogenase (IDH) 1 and 2 mutations fundamentally... |
The fifth edition of the World Health Organization (WHO) classification recognizes IDH‐mutant astrocytomas as a distinct entity encompassing Grades 2–4, with grading based on integrated histologic and molecular features [2]. Grade 2 tumors show diffuse infiltration with mild cellularity and nuclear atypia, achieving me... |
Historically, landmark glioma trials enrolled molecularly unselected cohorts, frequently combining astrocytic and oligodendroglial tumors and conflating IDH‐mutant and IDH‐wildtype diseases [2]. Reinterpretation of these studies alongside emerging prospective data has reshaped the evidence base for surgery, radiotherap... |
Existing guidelines have primarily focused on standard radiotherapy and chemotherapy regimens or individual advances such as IDH inhibition. While valuable, these resources often rely on the historical “low‐grade versus high‐grade” dichotomy, provide limited granularity on integrated risk models spanning WHO Grades 2–4... |
In this review, we synthesize current knowledge on IDH‐mutant astrocytomas through the dual lens of risk stratification and therapeutic advance. We first summarize contemporary concepts in molecular classification and diagnostics, emphasizing how histopathology, co‐mutational patterns, and advanced imaging define biolo... |
## Search Strategy and Study Selection |
This narrative review provides an expert synthesis integrating clinical, radiologic, pathologic, molecular, and translational evidence relevant to risk stratification and therapeutic advances in IDH‐mutant astrocytomas across CNS WHO Grades 2–4. We performed a structured literature search from January 2000 to October 2... |
### Data Sources and Eligibility Criteria |
We searched PubMed/MEDLINE, Embase, and Web of Science for English‐language articles, and screened ClinicalTrials.gov, the EU Clinical Trials Register, major meeting abstracts (ASCO, ESMO, SNO, ASTRO), and key guidelines (WHO CNS 2016/2021, EANO, NCCN, ASCO–SNO) for practice context and backward citation tracking. Sear... |
We prioritized adult IDH‐mutant diffuse astrocytomas classified under WHO 2016 or 2021 criteria. Eligible evidence included randomized trials, prospective/retrospective cohorts, pooled analyses, and large institutional series reporting outcomes or treatment effects. Translational and preclinical studies were included w... |
### Study Selection and Evidence Appraisal |
Titles/abstracts were screened for relevance, followed by full‐text review and assignment to prespecified domains (classification, risk stratification, standard therapies, targeted/immunologic strategies, resistance/recurrence). For overlapping cohorts, the most recent and comprehensive report was prioritized. |
Given the heterogeneity of included evidence, no formal risk‐of‐bias scoring was performed. Instead, evidence was weighted qualitatively by design, sample size, and follow‐up maturity, with randomized trials, large prospective studies, and consensus guidelines serving as anchors, and retrospective series/early‐phase tr... |
## Molecular Classification and Diagnostic Principles |
IDH defines the lineage; co‐alterations and late events define the clinical course. As summarized in Figure 1, IDH1/2 mutation with ATRX loss and TP53 inactivation establishes the early astrocytoma lineage program, while later events (including CDKN2A/B homozygous deletion) help define integrated CNS WHO Grades 2–4 and... |
### Foundational Genetics of IDH‐Mutant Astrocytomas |
High‐grade gliomas likely arise from neural precursor populations; accumulating evidence suggests that astrocyte‐like neural stem cells in the subventricular zone (SVZ), carrying low‐level somatic mutations, may serve as cells of origin [8, 9, 10, 11, 12, 13]. These tumors harbor multipotent glioma stem‐like cells with... |
In WHO Grade 2 IDH‐mutant astrocytomas, three recurrent, early cooperating alterations form the canonical genetic backbone: IDH1/2 mutation, ATRX inactivation, and TP53 loss. |
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