Distinct molecular profile and outcome of oligodendroglioma, IDH-mutant, 1p/19q-codeleted, and TERTp-wildtype: A grade 1 oligodendroglioma of young patients?

Neuro Oncol. 2025 Oct 1;27(10):2711-2725. doi: 10.1093/neuonc/noaf141.

Abstract

Background: Oligodendrogliomas, characterized by isocitrate dehydrogenase (IDH) mutations and 1p/19q codeletion, often exhibit telomerase reverse transcriptase promoter (TERTp) mutations, which have been linked to telomere maintenance (TM) and tumor proliferation. Although there are a few reports on a TERTp-wildtype subset of these tumors in adolescents and young adults, the frequency, molecular characteristics, and prognostic implications of TERTp-wildtype status in oligodendrogliomas remain elusive.

Methods: We retrospectively analyzed 166 IDH-mutant and 1p/19q-codeleted oligodendroglioma cases through comprehensive histopathological review and molecular analyses, including Sanger sequencing, DNA methylation profiling, and whole-exome sequencing (WES).

Results: A TERTp-wildtype status was observed in 20/166 cases (12.0%) and was significantly associated with noticeably young age (age range: 14-27, P < .001), CNS WHO grade 2 (P = .003), and the absence of additional DNA copy number variations (CNVs) beyond the pathognomonic 1p/19q codeletion (P < .001). Epigenetic profiling demonstrated TERTp-wildtype tumors shaped a distinct subgroup at the utmost periphery of TERTp-mutant oligodendrogliomas. Methylation analysis of the upstream and proximal TERTp regions revealed that, in line with the absence of genetic alterations, epigenetic regulation does not favor TERT overexpression in TERTp-wildtype oligodendrogliomas. WES showed no TM-related gene alterations in TERTp-wildtype cases. Cox regression analysis confirmed TERTp-wildtype status as an independent prognostic factor for more favorable progression-free survival (PFS) (P = .009).

Conclusions: In conclusion, "oligodendroglioma, IDH-mutant, 1p/19q-codeleted, and TERTp-wildtype" represent a distinct molecular subgroup associated with younger age and a better clinical course compared to CNS WHO grade 2 oligodendrogliomas.

Keywords: TERT promoter; adolescents and young adults; methylation; oligodendroglioma; progression-free survival.

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers, Tumor* / genetics
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / mortality
  • Brain Neoplasms* / pathology
  • Chromosome Deletion
  • Chromosomes, Human, Pair 1* / genetics
  • Chromosomes, Human, Pair 19* / genetics
  • DNA Copy Number Variations
  • DNA Methylation
  • Female
  • Follow-Up Studies
  • Humans
  • Isocitrate Dehydrogenase* / genetics
  • Male
  • Mutation*
  • Neoplasm Grading
  • Oligodendroglioma* / genetics
  • Oligodendroglioma* / mortality
  • Oligodendroglioma* / pathology
  • Prognosis
  • Promoter Regions, Genetic
  • Retrospective Studies
  • Survival Rate
  • Telomerase* / genetics
  • Young Adult

Substances

  • Telomerase
  • Isocitrate Dehydrogenase
  • TERT protein, human
  • Biomarkers, Tumor