Diffuse Glioma (DIFG)

Overview

OncoTree parent for adult diffuse gliomas, including IDH-mutant astrocytoma (ASTR) and oligodendroglioma (ODG).

Cohorts in the corpus

  • difg_msk_2023 — 128 adult patients at MSKCC with WHO 2016 Grade 2 IDH-mutant astrocytoma or oligodendroglioma on active surveillance; 73/128 profiled by MSK-IMPACT PMID:37910594.
  • csf_msk_2024 — Gliomas were the third most common tumor type in the MSK CSF ctDNA cohort (n=148 patients), including diffuse gliomas profiled by MSK-IMPACT on CSF samples PMID:39289779.
  • Bakas 2017 published expert MRI segmentations and radiomic features for the TCGA-LGG collection (IDH-mutant lower-grade gliomas, a subset of diffuse gliomas), providing multiparametric MRI with manually delineated tumor sub-region labels and extracted radiomic features alongside the TCGA-GBM dataset PMID:28872634.

Recurrent alterations

  • IDH1/IDH2 mutation required for cohort inclusion; verified by IHC (93.8%) and/or NGS (57%) PMID:37910594.
  • CDKN2A/B homozygous deletion defines “molecular grade-high” IDH-mt glioma (WHO 2021 Grade 4 astrocytoma) and drove ~2× faster tumor-volume growth rate (19.17% vs 9.54% per 6 months) PMID:37910594.
  • Focal amplifications of MYCN, CDK4, PDGFRA defined “molecular grade-intermediate” in 1p19q intact tumors PMID:37910594.
  • IDH1 p.R132H detected in CSF ctDNA from IDH-mutant gliomas PMID:39289779.
  • H3-3A p.K28M histone mutation supporting diagnosis of diffuse midline glioma detected in CSF ctDNA PMID:39289779.
  • BRAF::KIAA1549 fusions detected in CSF ctDNA from gliomas PMID:39289779.
  • Temozolomide mutational signatures identified in CSF ctDNA from glioma samples among high-TMB cases PMID:39289779.
  • Exome sequencing of 23 paired initial/recurrent grade II diffuse gliomas showed pervasive early clonal branching; IDH1 R132H was the only mutation shared in every patient pair, confirming it as the initiating event in low-grade gliomagenesis PMID:24336570.
  • TCGA pan-glioma study (n=1,122 grade II-IV diffuse gliomas) identified 75 significantly mutated genes including novel drivers SETD2, ARID2, DNMT3A, KRAS, NRAS; six methylation subclusters (LGm1–6) provide an independent prognostic classification on top of age and grade PMID:26824661
  • PIPseq cohort included diffuse intrinsic pontine glioma cases; H3-3A (H3F3A) K27M mutation identified as HDAC-inhibitor target; paired with FGFR1 N577K in one patient PMID:28007021

Subtypes

  • 1p19q codeleted oligodendroglioma (n=69, 53.9%) and 1p19q intact astrocytoma (n=59, 46.1%) PMID:37910594.
  • Molecular grade-high (CDKN2A/B homozygous deletion, n=4) behaves aggressively on imaging even during watch-and-wait PMID:37910594.

Therapeutic landscape

  • Tumor volume growth rate (TVGR) on volumetric MRI proposed as an earlier surrogate endpoint for active-surveillance trials of IDH-targeted therapies PMID:37910594.
  • Standard treatment (temozolomide and/or radiotherapy) in IDH-mutant gliomas 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 identified as master regulator of IDH-mutant astrocytoma progression; CRISPR knockout decreased cell proliferation PMID:38117484.

Sources

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