TCGA Glioblastoma 2013 (Publication Freeze)

Overview

Multi-platform genomic, transcriptomic, epigenomic, and proteomic dataset for 543 primary glioblastoma (GBM) patients assembled by The Cancer Genome Atlas (TCGA), with data frozen on 2013-07-15. This 2013 publication freeze substantially expanded the 2008 TCGA GBM study by adding whole-exome sequencing (291 pairs), whole-genome sequencing (42 deep-coverage pairs), RNA-seq (164 transcriptomes), expanded DNA methylation arrays, and reverse-phase protein arrays (214 samples, 171 antibodies). The corresponding cBioPortal study is gbm_tcga_pub2013. Primary publication: Brennan et al. Cell 2013.

Composition

  • Cancer type: GBM — primary glioblastoma multiforme.
  • Samples: 543 primary GBM patients accrued from 17 TCGA contributing sites, diagnosed 1989–2011.
  • Demographics: median age 59.6 years; M:F = 1.6 (333:209).
  • Survival: median OS 13.9 months; 2-year survival 22.5%; 5-year 5.3%.
  • Treatment: 40% (217/543) received concurrent TMZ + radiation; 50.2% of those diagnosed ≥2002.
  • IDH1 mutation frequency: 6% (28/423 with adequate coverage). PMID:24120142

Assays / panels (linked)

  • whole-exome-seq — 291 tumor/normal pairs; Agilent SureSelect 50 Mb hybrid capture; 138× mean target coverage; Illumina GA2000/HiSeq; 98% SNV validation rate.
  • whole-genome-seq — 42 deep-coverage tumor/normal pairs; structural variant callers breakdancer and bambam.
  • rna-seq — 164 transcriptomes; analyzed with prada for fusion detection.
  • rppa — 214 samples, 171 antibodies; pathway-level protein and phosphoprotein profiling.
  • hm27-methylation-array — 283 samples (91 reanalyzed).
  • hm450-methylation-array — 76 samples in publication freeze; 113 in re-analysis.
  • illumina-goldengate — DNA methylation, 238 samples.
  • DNA copy-number arrays (aCGH) — 492 samples; SCNA peaks by gistic.
  • Significance calling: mutsig and invex; mutual exclusivity: memo.

Papers using this cohort

  • PMID:24120142 — Brennan CW et al., “The Somatic Genomic Landscape of Glioblastoma”, Cell 2013.

Notable findings derived from this cohort

  • 71 significantly mutated genes identified by MutSig + InVEx, including the novel driver LZTR1 (mutated in 10 samples) and known drivers EGFR, PTEN, TP53, PIK3CA, NF1, RB1, IDH1, PDGFRA. PMID:24120142
  • EGFR is altered in 57% of GBM; EGFRvIII (exon 2–7 deletion) at ≥10% TAF in 11%; diverse co-existing alteration forms (EGFRvIII, C-terminal deletions, Δ12–13, point mutations) suggest intratumoral heterogeneity will complicate single-agent targeting. PMID:24120142
  • TERT promoter mutations (C228T/C250T) detected in 84% of deep-coverage WGS cases; all non-TERT-mutant cases harbored ATRX mutations, defining a binary telomere-maintenance dichotomy. PMID:24120142
  • MGMT promoter methylation (48.5% of cohort) predicts temozolomide response specifically in the classical transcriptomic subtype (P=0.01) but not in proneural, mesenchymal, or neural subtypes. PMID:24120142
  • Proneural-subtype survival advantage is attributable to the G-CIMP+ epigenotype, not the transcriptomic subtype per se; non-G-CIMP proneural tumors behave like other subtypes. PMID:24120142
  • RPPA data reveal non-linear genotype-to-signaling relationships: RTK-amplified samples show lower downstream phospho-AKT/S6K/MAPK; PI3K-mutant samples show lower AKT activity than PI3K-WT — complicating pathway-level therapeutic rationale. PMID:24120142

Sources

  • cBioPortal study: gbm_tcga_pub2013
  • PMID:24120142 — primary publication
  • Data freeze date: 2013-07-15

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