Lung Adenocarcinoma (Broad, Nature Genetics 2012)

Overview

183 lung adenocarcinoma tumour-normal pairs (159 WES, 24 WGS, with 23 having both) characterised at the Broad Institute. Published in Nature Genetics 2012. The study identified 25 significantly mutated genes, confirmed EGFR/KRAS/STK11 as major drivers, and nominated novel driver genes RBM10, U2AF1, and ARID1A. A novel oncogenic EGFR C-terminal in-frame deletion was also discovered. PMID:22980975

Composition

  • 183 LUAD tumour-normal pairs.
  • 159 cases with WES (median 92x exome coverage, range 51–201x); 24 with WGS (median 69x tumour, 36x normal); 23 cases had both.
  • Clinical composition: 27 never smokers, 17 light smokers, 118 heavy smokers, 21 unknown; stages I-IV.
  • Complementary SNP array analysis for somatic copy number alterations. PMID:22980975

Assays / panels (linked)

  • whole-exome-seq — 159 tumour-normal pairs (median 92x)
  • whole-genome-seq — 24 tumour-normal pairs (median 69x tumour)
  • mutsig — significantly mutated gene analysis (InVEx/MutSig); 25 genes at q < 0.25

Papers using this cohort

  • PMID:22980975 — primary characterisation study (Imielinski et al., Nature Genetics 2012)
  • PMID:27158780 — Campbell et al. 2016, Nature Genetics: 159 cases from this cohort incorporated into the integrated 1,144-NSCLC exome analysis nsclc_tcga_broad_2016.

Notable findings derived from this cohort

  • Mean exonic somatic mutation rate 12.0 mutations/Mb (median 8.1/Mb; range 0.04–117.4/Mb); smokers significantly higher than never smokers (median 9.8 vs 1.7/Mb; P = 3.0×10^-9). PMID:22980975
  • 25 significantly mutated genes (q < 0.25) including known drivers EGFR, KRAS, TP53, STK11, KEAP1, NF1, BRAF. PMID:22980975
  • U2AF1 p.S34F hotspot mutation in 3% of cases (first report in an epithelial tumour); associated with reduced progression-free survival (P = 0.00011, log-rank). PMID:22980975
  • RBM10 mutated in 7% with recurrent truncating mutations. PMID:22980975
  • ARID1A mutated in 8% with significant accumulation of truncating mutations. PMID:22980975
  • Novel oncogenic EGFR C-terminal in-frame deletion discovered. PMID:22980975
  • 159 cases from this cohort merged into the integrated nsclc_tcga_broad_2016 Pan-Lung analysis alongside TCGA ADC/SqCC cases; used to maximize statistical power for rare-driver discovery in the 660-ADC analysis. PMID:27158780

Sources

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