Glioblastoma, IDH-Wildtype (GB)

Overview

Glioblastoma, IDH-wildtype (GB) is the most common and aggressive primary brain tumor in adults, characterized by IDH-wildtype status and WHO grade 4 designation. On OncoTree it is a child of Adult Diffuse Glioma (ADIFG). It is distinguished from IDH-mutant astrocytoma by its wild-type IDH status, distinct epigenetic profile, and uniformly aggressive clinical course.

Cohorts in the corpus

  • Interim integrative analysis of 206 newly diagnosed glioblastoma (GBM) cases from The Cancer Genome Atlas (TCGA), with 91 cases undergoing nucleotide sequence analysis. PMID:18772890
  • 60 IDH-wildtype glioblastoma patients from the GLASS International consortium (difg_glass), with matched initial and first-recurrent DNA methylation data (Illumina 450K/EPIC arrays). PMID:38117484
  • LN229 (EGFR−/low, GB cell line): negative-control model in ADC radiosensitization study — C-MMAE did not accumulate in LN229 xenografts and did not radiosensitize LN229 cells in vitro, confirming receptor-selectivity requirement. PMID:27698471
  • Bakas 2017 published expert MRI segmentations and radiomic features for the TCGA-GBM collection (n=262 IDH-wildtype glioblastoma cases), providing multiparametric MRI (T1, T1Gd, T2, FLAIR) with manually delineated tumor sub-region labels and extracted radiomic features PMID:28872634.

Recurrent alterations

  • Nearly all GBMs (88-90%) exhibit alterations in three core signaling pathways: RTK/RAS/PI3K (88% of cases; EGFR, NF1, PTEN, PIK3R1), p53 (78% of cases; TP53, MDM2, CDKN2A), and RB (88% of cases; RB1, CDKN2A/B, CDK4). PMID:18772890
  • PIK3R1 — frequent mutations (10%) identified in GBM, often in the iSH2 domain, which disrupt p110α interaction and activate the PI3K pathway. PMID:18772890
  • NF1 — somatic mutations and deletions occur in 18% of cases, identifying it as a major tumor suppressor in GBM. PMID:18772890
  • Extracellular domain mutations in EGFR (novel missense) and ERBB2 (8% of cases) contribute to RTK pathway activation. PMID:18772890
  • IDH-wildtype status defines GB: these tumors maintain stable epigenomes over time, with low global methylation at both initial diagnosis and recurrence (zero CpG probes showing differential methylation >15% between initial and recurrent tumors). PMID:38117484
  • TERT — mutations co-occur with BRAF fusions in gliomas (11% co-occurrence); TERT mutations found in glioma subset. PMID:38922339
  • EGFR — amplification is a hallmark of IDH-wildtype glioblastoma (not specifically quantified in these corpus studies).
  • EGFR low/absent expression in LN229 GB cells prevents C-MMAE binding, accumulation, and radiosensitization — confirms that EGFR expression level, not mere tumor histology, gates ADC activity. PMID:27698471
  • Re-analysis of 48 pediatric GB exomes identified 3/48 (6%) cases with the triple-mutation constellation FGFR1 activation + H3-3A K27M + NF1 alteration (all TP53-wildtype), extending FGFR-targeted therapy rationale to a subset of pediatric glioblastoma PMID:23817572
  • Glioblastoma was included in the MSK-IMPACT pan-cancer cohort; TP53 was significantly enriched in glioblastoma vs TCGA primary tumors; EGFRvIII (exon 2-7 deletion) was detected in 65 cases and EGFR mutations localized to the extracellular N-terminal domain in glioma vs kinase domain in lung cancer. PMID:28481359

Subtypes

  • IDH-wildtype glioblastoma has a stable epigenome compared to IDH-mutant gliomas, which undergo progressive demethylation at recurrence. PMID:38117484
  • BRAF fusions occur at low frequency (<1%) across gliomas; pilocytic astrocytoma (a pediatric low-grade glioma, not GB) has 56% BRAF fusion prevalence; adult IDH-wildtype GB is not specifically enriched for BRAF fusions. PMID:38922339

Therapeutic landscape

  • MGMT promoter methylation is a biomarker for response to alkylating agents like temozolomide. PMID:18772890
  • Recurrent GBMs treated with temozolomide may develop a hypermutator phenotype if they possess both MGMT promoter methylation and mutations in mismatch repair genes (e.g., MSH6). PMID:18772890
  • Effective GBM treatment likely requires combination therapies targeting multiple core pathways (RTK, p53, RB). PMID:18772890
  • Unlike IDH-mutant gliomas, IDH-wildtype GB does not show treatment-induced epigenetic evolution at recurrence; epigenomic stability means the tumor biology at recurrence resembles the primary tumor. PMID:38117484
  • EGFR-directed ADC radiosensitization (C-MMAE) requires sufficient receptor surface expression; LN229 (EGFR-low GB) xenografts showed no C-MMAE accumulation by Cy5 fluorescence imaging and no radiosensitization, highlighting that not all GB tumors will be susceptible to EGFR-directed ADC approaches. PMID:27698471

Sources

This page was processed by entity-page-writer on 2026-05-15.