Oligodendroglioma (ODG)

Overview

Oligodendroglioma, a 1p19q-codeleted IDH-mutant diffuse glioma subtype (parent DIFG).

Cohorts in the corpus

  • difg_msk_2023 — 69 (53.9%) 1p19q codeleted oligodendrogliomas in the MSKCC IDH-mutant low-grade glioma active-surveillance cohort PMID:37910594.
  • difg_glass — 13 1p/19q-codeleted ODG patients in the GLASS International consortium longitudinal methylation study. PMID:38117484
  • 6 untreated grade II oligodendrogliomas (MGH36, MGH53, MGH54, MGH60, MGH93, MGH97), all IDH1/IDH2 mutant and 1p/19q co-deleted, profiled by Smart-seq2 single-cell RNA-seq (4,347 cells total); external validation in 69 bulk TCGA LGG oligodendroglioma samples. PMID:27806376

Recurrent alterations

  • TERT promoter mutations in 100%, CIC mutations in 42%, FUBP1 mutations in 24% of 1p19q codeleted oligodendrogliomas sequenced by MSK-IMPACT PMID:37910594.
  • No significant TVGR difference vs 1p19q intact astrocytomas during active surveillance (codeleted 9.62% vs intact 11.73% per 6 months, P=0.16), suggesting the survival advantage of codeleted tumors may be driven by chemosensitivity rather than slower natural history PMID:37910594.
  • IDH1 / IDH2 mutations define the GCIMP phenotype in ODG; IDH-mutant gliomas (including ODG) showed genome-wide loss of DNA methylation at recurrence in the GLASS longitudinal study. PMID:38117484
  • Unlike astrocytoma, ODG did not show the HOXD13-driven progression signature; the GLASS DIFG cohort included only 13 ODG patients with matched primary/recurrent methylation data. PMID:38117484
  • Single-cell profiling of 4,347 cells from 6 grade II ODG tumors reveals a three-compartment developmental hierarchy: oligodendrocyte-like (OLIG1/OLIG2/OMG high), astrocyte-like (APOE/ALDOC/SOX9 high), and a rare stem/progenitor compartment (SOX2/SOX4/SOX11 high) that accounts for nearly all proliferating cells (1.5–8% per tumour). PMID:27806376
  • IDH1/IDH2 mutations and 1p/19q co-deletion confirmed in all 6 tumors; subclonal CIC mutation (~30% VAF) in MGH53 upregulates ETV1/ETV5. CNV subclones and point mutations span all three developmental compartments, arguing that ODG architecture is primarily driven by non-genetic, developmental programs. PMID:27806376
  • CCND2 is preferentially expressed in the stem/progenitor compartment; differentiated cells express CCND1/CCND3 — mirroring normal neural development. PMID:27806376
  • TCGA pan-glioma study included 174 oligodendroglioma cases (17% of 1,122-patient cohort); oligodendroglioma corresponds to the Codel (1p/19q co-deleted, IDH-mutant) subgroup with methylation cluster LGm1–3 and best-prognosis outcome PMID:26824661
  • 1p/19q codeletion was a significant predictor of PFS (P=0.03) and OS (P<0.001) in the odg_msk_2017 phase II trial (n=33 codeleted patients: 5-year PFS 50.3%, 5-year OS 93.4%); 1p/19q-intact tumors displayed glioblastoma-like NGS signatures (EGFR amplification, NF1, MDM2; IDH1/2 wild-type) and progressed early, arguing against chemotherapy-only strategies without codeletion. PMID:28472509

Subtypes

  • T2-FLAIR mismatch sign absent in 96.9% of codeleted oligodendrogliomas PMID:37910594.
  • The stem/progenitor transcriptional program in grade II ODG more closely resembles a tri-potent neural progenitor than an OPC, suggesting a neural-progenitor-like cell of origin; this was not functionally validated by xenotransplantation. PMID:27806376

Therapeutic landscape

  • TVGR proposed as surrogate endpoint for active-surveillance trials of IDH-targeted therapy PMID:37910594.
  • The rare stem/progenitor compartment (SOX2/SOX4/SOX11-high, 1.5–8% of cells) is the primary proliferative reservoir and is a plausible therapeutic target; differentiated oligo-like and astro-like cells are largely non-cycling. Targeting the OPC compartment alone may miss the proliferative apex. PMID:27806376

Sources

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