Astrocytoma, IDH-Mutant (ASTR)

Overview

IDH-mutant astrocytoma (ASTR) is a diffuse glioma subtype defined by IDH1/IDH2 mutation and absence of 1p/19q codeletion (distinguishing it from oligodendroglioma). It sits within the Adult Diffuse Glioma (ADIFG) group on OncoTree. WHO grade is determined by molecular features including CDKN2A/B homozygous deletion (grade 4).

Cohorts in the corpus

  • 59 IDH-mutant astrocytoma patients from the GLASS International consortium (difg_glass), with matched initial and first-recurrent paired DNA methylation data (Illumina 450K/EPIC arrays). PMID:38117484
  • difg_msk_2023 — 59 (46.1%) 1p19q intact IDH-mutant astrocytomas in the MSKCC active-surveillance cohort PMID:37910594.

Recurrent alterations

  • IDH1 / IDH2 mutations — define the GCIMP hypermethylation phenotype; IDH-mutant astrocytomas undergo progressive epigenetic demethylation at recurrence, especially after treatment. PMID:38117484
  • CDKN2A — homozygous deletion is a diagnostic molecular marker for CNS WHO grade 4 IDH-mutant astrocytoma; acquisition at recurrence associated with radiotherapy. PMID:38117484
  • MGMT — promoter methylation relevant to temozolomide response. PMID:38117484
  • HOXD13 — identified as a master regulator of IDH-mutant astrocytoma progression; gained H3K27ac and H3K4me3 marks at recurrence; CRISPR KO reduced proliferation. PMID:38117484
  • MSH6 — somatic mutations in recurrent gliomas linked to hypermutation phenotype after alkylator chemotherapy. PMID:38117484
  • TP53 mutations in 94% and ATRX mutations in 77% of 1p19q intact IDH-mt astrocytomas in the MSK-IMPACT subcohort PMID:37910594.
  • PIK3R1 and PIK3CA mutations (with TP53 and broad CNV load) used to define “molecular grade-intermediate” in 1p19q intact tumors PMID:37910594.
  • Cohort of 23 paired initial/recurrent grade II astrocytomas revealed that in 43% of cases at least half of initial-tumor driver mutations (including IDH1 R132H — universal) were absent at recurrence, and 6 of 10 temozolomide-treated patients developed hypermutated recurrences that all progressed to GBM PMID:24336570.
  • TCGA pan-glioma study included 169 astrocytoma cases (16% of 1,122-patient cohort); astrocytoma enriched for IDH-mutant G-CIMP-high and G-CIMP-low methylation subtypes; G-CIMP-low (IDH-mutant non-codel) subset identified as poor-prognosis entity with cell-cycle gene activation (CDK4, CDKN2A) PMID:26824661

Subtypes

  • GCIMP-high vs. GCIMP-low: 71% (10/14) of IDH-mutant tumors switching subtypes transitioned from GCIMP-high to GCIMP-low at recurrence, associated with worse overall survival (log-rank P=0.06). 34% of GCIMP-high tumors in the treatment group progressed to GCIMP-low vs. 4% in the non-treatment group (Fisher test, P=0.005). PMID:38117484
  • 68% (15/22) of IDH-mutant astrocytomas progressed to high-grade (WHO grade 4) in the treatment group vs. 23% (6/26) in the non-treatment group (Fisher test, P=0.003). PMID:38117484
  • Molecular grade (low / intermediate / high) based on MYCN/CDK4/PDGFRA amplification and CDKN2A/B deletion status PMID:37910594.

Therapeutic landscape

  • Standard treatment (temozolomide and/or radiotherapy) delays progression (PFI 40.5 vs. 27 months, P=0.009) but is associated with epigenetic evolution toward an aggressive, IDH-wildtype-like phenotype at recurrence; survival from second surgery is markedly worse in previously treated patients (log-rank P=0.0001). PMID:38117484
  • HOXD13 and downstream targets (CENPF, PCNA) represent potential therapeutic targets in recurrent IDH-mutant glioma. PMID:38117484

Sources

  • PMID:38117484 — The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen (Cancer Research, 2024)
  • PMID:37910594 — Tumor Volume Growth Rates and Doubling Times during Active Surveillance of IDH-mutant Low-Grade Glioma (Clinical Cancer Research, 2024)
  • PMID:24336570
  • PMID:26824661

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