NSCLC Integrated Exome Cohort (Campbell et al. 2016)

Overview

Integrated exome-sequencing cohort combining 660 lung adenocarcinoma (ADC) and 484 lung squamous cell carcinoma (SqCC) tumor/normal pairs (1,144 NSCLCs total), assembled from three sources: 274 previously unpublished ADC and 308 previously unpublished SqCC cases contributed directly, merged with 227 TCGA ADC cases (luad_tcga_pub), 159 Imielinski/Broad ADC cases (luad_broad), and 176 TCGA SqCC cases (lusc_tcga_pub). The study was designed to achieve sufficient power to identify drivers rare in each histology and to comprehensively compare molecular landscapes across NSCLC subtypes. PMID:27158780

Composition

  • Cancer types: LUAD and LUSC
  • 660 lung ADC + 484 lung SqCC tumor/normal exome pairs = 1,144 total
  • RNA-seq available for 495 ADC and 476 SqCC
  • SNP-array copy number on Affymetrix SNP 6.0 for all cases
  • Expert pathology review performed on a 227-tumor ADC subset
  • Median somatic mutation rate 8.7/Mb (ADC) and 9.7/Mb (SqCC) PMID:27158780

Assays / panels (linked)

Papers using this cohort

  • PMID:27158780 — Campbell et al. 2016, Nature Genetics — “Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas”; primary discovery study.

Notable findings derived from this cohort

  • MutSig2CV identified 38 significantly mutated genes in lung ADC and 20 in lung SqCC (q < 0.1); only 6 genes shared between histologies (TP53, RB1, ARID1A, CDKN2A, PIK3CA, NF1). PMID:27158780
  • Lung SqCC molecular landscape more closely resembles HNSC and BLCA (>25% SMG overlap) than lung ADC (~12% overlap), reinforcing histological treatment distinctions. PMID:27158780
  • Six mutational signatures identified: COSMIC SI4 (smoking, C>A), SI7 (UV), SI13/SI2 (APOBEC), SI15/SI6 (MMR), SI5 (clock-like); smoking SI4 distinguished never- vs ever-smokers in ADC (AUC=0.87) but not in SqCC (AUC=0.62). PMID:27158780
  • Novel significantly mutated genes: PPP3CA and DOT1L in ADC; RASA1 and CUL3 in SqCC; KLF5, EP300, CREBBP, B2M in Pan-Lung analysis. PMID:27158780
  • 242 oncogene-negative lung ADCs — adding SOS1, VAV1, RASA1, ARHGAP35 and novel amplification targets raised the fraction of ADC with a defined RTK/Ras/Raf driver from ~62% to 76% overall (85% in expert-reviewed subset). PMID:27158780
  • Novel focal amplifications: MIR21/TUBD1 and CCND3 in ADC; YES1 and MIR205 in SqCC; MAPK1 in Pan-Lung. PMID:27158780
  • 47% of lung ADC and 53% of lung SqCC tumors had ≥5 predicted neoepitopes, supporting broad immunotherapy applicability across both NSCLC histologies. PMID:27158780
  • Neoepitope load significantly lower in never-smoker vs ever-smoker ADCs (P<0.001), but did not differ between ever-smoker ADCs and SqCCs. PMID:27158780

Sources

  • cBioPortal studyId: nsclc_tcga_broad_2016
  • Campbell JD et al. “Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.” Nature Genetics. 2016;48(6):607-616. PMID:27158780. DOI: 10.1038/ng.3564.

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