Glioblastoma Multiforme (GBM)

Overview

Glioblastoma Multiforme (GBM) is a highly aggressive and common primary brain tumor. In the OncoTree hierarchy, it is categorized under Diffuse Glioma (DIFG). In modern clinical practice and newer classification systems (e.g., WHO 2021), it is often discussed interchangeably with Glioblastoma, IDH-Wildtype (GB), which represents the majority of cases historically diagnosed as GBM.

Cohorts in the corpus

Recurrent alterations

Nearly all GBMs (88-90%) exhibit alterations in three core signaling pathways:

  • RTK/RAS/PI3K pathway (88% of cases):
    • EGFR: Amplified in 45% of cases; also harbors novel missense mutations in the extracellular domain PMID:18772890.
    • PTEN: Frequently inactivated through mutation or deletion (36%) PMID:18772890.
    • NF1: Somatic mutations and deletions occur in 18% of cases, identifying it as a major tumor suppressor in GBM PMID:18772890.
    • PIK3R1: Frequent mutations (10%) disrupt p110α interaction and activate the PI3K pathway PMID:18772890.
    • Other alterations include ERBB2 (8%), PIK3CA (7%) PMID:18772890.
  • p53 pathway (78% of cases):
  • RB pathway (88% of cases):
  • TCGA 2013 multi-platform analysis of 543 primary GBM identified 71 significantly mutated genes; EGFR altered in 57% (rearrangements, EGFRvIII, novel splice variants); TERT promoter mutations in 84% of deep-coverage cases; MGMT methylation predicted TMZ response only in classical subtype; proneural survival advantage attributable to G-CIMP epigenotype PMID:24120142.
  • All 6 hypermutated recurrent grade II astrocytomas (arising after temozolomide therapy) progressed to GBM, acquiring TMZ-signature driver mutations in the RB and AKT–mTOR pathways (RB1, CDKN2A, PIK3CA, PTEN, MTOR), with validated in vivo mTORC1 hyperactivation PMID:24336570.
  • TCGA pan-glioma study included 590 GBM cases (56% of 1,122-patient cohort); GBM enriched for TERTp mutations, chr7 gain/chr10 loss, and IDH-wildtype methylation subtypes (Classic-like, Mesenchymal-like, LGm6-GBM); LGm6-GBM cluster had MAPK-pathway alterations in 32% of cases PMID:26824661
  • MC3 pan-cancer mutation-calling project (10,510 TCGA pairs) included GBM as one of 33 cancer types; the MC3 MAF provides the somatic variant backbone for gbm_tcga_pan_can_atlas_2018 in cBioPortal PMID:29596782
  • Pan-cancer fusion study (9,624 TCGA samples) included GBM; GBM fusions included chromosome 7 gains in IDH-wildtype GBM; druggable fusions covered 6% of pan-can samples including GBM PMID:29617662
  • Pan-cancer aneuploidy study found GBM has the highest rate of any arm-level event (99% of samples, mean score 8.2); IDH-wildtype GBM is characterized by chromosome 7 gain and chromosome 10 loss; GBM clusters in the neural-lineage arm-level group with LGG and melanoma PMID:29622463

Subtypes

  • Hypermutator phenotype: Identified in recurrent GBMs treated with temozolomide that harbor both MGMT promoter methylation and mismatch repair (MMR) deficiencies (e.g., MSH6 mutations) PMID:18772890.

Therapeutic landscape

  • Alkylating agents: Temozolomide is a standard treatment; MGMT promoter methylation is a biomarker for response PMID:18772890.
  • Combination therapies: Analysis of core pathway alterations suggests that effective treatment likely requires targeting multiple components within the RTK/RAS/PI3K, p53, and RB pathways PMID:18772890.

Sources

  • PMID:18772890 — Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008.
  • PMID:28872634 — Bakas S, et al. Advancing The Cancer Genome Atlas glioma MRI collections with expert segmentation labels and radiomic features. Sci Data. 2017.
  • PMID:24120142
  • PMID:24336570
  • PMID:26824661

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