Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Author

The Cancer Genome Atlas (TCGA) Research Network

Doi

10.1038/nature07385

TL;DR

The Cancer Genome Atlas (TCGA) Research Network presents an interim integrative analysis of 206 glioblastomas (GBM), identifying key genetic alterations across three core pathways: RTK/RAS/PI3K (88%), p53 (78%), and RB (88%). The study highlights frequent PIK3R1 mutations and establishes a link between MGMT promoter methylation and a mismatch repair-deficient hypermutator phenotype in treated tumors.

Cohort & Data

  • Samples: 206 newly diagnosed glioblastoma (GBM) cases.
  • Profiling:
    • DNA copy number, gene expression, and DNA methylation analyzed in all 206 cases.
    • Nucleotide sequence aberrations analyzed in 91 of these cases.
    • 143 cases had matched normal peripheral blood DNA.
  • Criteria: Minimum 80% tumor nuclei and maximum 50% necrosis.

Key Findings

  • Significantly Mutated Genes: Identified eight genes with a false discovery rate <0.1: TP53, PTEN, NF1, EGFR, ERBB2, RB1, PIK3R1, and PIK3CA.
  • Core Pathways: The analysis revealed that nearly all GBMs are altered in three core signaling pathways:
    • RTK/RAS/PI3K pathway (88% of samples): Frequent alterations in EGFR (45%), ERBB2 (8%), NF1 (18%), PIK3R1 (10%), PIK3CA (7%), and PTEN (36%).
    • p53 pathway (78% of samples): Alterations in TP53 (35%), MDM2 (14%), MDM4 (7%), and CDKN2A (p14ARF) (49%).
    • RB pathway (88% of samples): Alterations in RB1 (11%), CDKN2A (p16INK4A), CDKN2B (52%), CDK4 (18%), CDK6 (1%), and CCND2 (2%).
  • PIK3R1 Mutations: Discovered frequent mutations in PIK3R1 (encoding the p85α regulatory subunit of PI3K), mostly in the iSH2 domain, which disrupt the interaction with p110α and lead to pathway activation.
  • NF1 Alterations: Somatic mutations and deletions of NF1 were identified in 18% of cases, establishing it as a major tumor suppressor in GBM.
  • Hypermutator Phenotype: In tumors treated with alkylating agents (temozolomide), MGMT promoter methylation combined with mutations in mismatch repair (MMR) genes (e.g., MSH6) was associated with a hypermutator phenotype.

Genes & Alterations

  • EGFR: Amplified in 45% of cases; also harbors novel missense mutations in the extracellular domain.
  • ERBB2: Mutations found in 8% of GBMs, primarily in the extracellular domain, suggesting a role in RTK activation.
  • NF1: Inactivated through both homozygous deletions and somatic mutations.
  • PIK3R1: Mutations in 10% of cases, often in the iSH2 domain (e.g., N564, D560).
  • TP53/PTEN/RB1: Frequent targets of both mutation and deletion.
  • CDKN2A/B: Homozygous deletion of the CDKN2A/CDKN2B locus is extremely common (over 50%).

Clinical Implications

  • Treatment Response: MGMT methylation is a potential biomarker for response to alkylating agents but also serves as a prerequisite for the development of a hypermutator phenotype upon tumor recurrence after treatment with temozolomide if mismatch repair is compromised.
  • Targeted Therapy: The identification of core pathway alterations suggests that combination therapies targeting multiple components within the RTK/RAS/PI3K, p53, and RB pathways may be necessary for effective treatment.

Limitations & Open Questions

  • Interim Analysis: The sequencing results were based on a subset (91 cases) of the total cohort.
  • Secondary GBM: The study focused on newly diagnosed (primary) GBM; secondary GBM was not a primary focus.
  • Hypermutation Mechanism: The specific sequences of events leading from MGMT methylation to MMR deficiency and hypermutation in treated samples warrant further longitudinal study.

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