Comprehensive genomic characterization of squamous cell lung cancers

Author

The Cancer Genome Atlas Research Network

Doi

10.1038/nature11404

PMID: 22960745 · DOI: 10.1038/nature11404 · Journal: Nature (2012)

TL;DR

The Cancer Genome Atlas comprehensively profiled 178 lung squamous cell carcinomas (LUSC) using whole-exome sequencing, whole-genome sequencing, RNA-seq, copy number arrays, and methylation arrays. The study identified statistically recurrent mutations in 18 genes including near-universal TP53 mutation (81-90%), novel loss-of-function mutations in HLA-A, and defined key altered pathways: NFE2L2/KEAP1 (34%), squamous differentiation (44%), PI3K/AKT (47%), and CDKN2A/RB1 (72%). A potential therapeutic target was identified in the majority (64%) of tumors.

Cohort & data

  • 178 previously untreated stage I-IV lung squamous cell carcinomas (LUSC)
  • Dataset: lusc_tcga_pub
  • 96% of patients had a history of tobacco use; median follow-up 15.8 months
  • Platforms: whole-exome sequencing (178 tumors + matched normals, mean 121X coverage), whole-genome sequencing (19 pairs, mean 54X), RNA-seq (178 samples), miRNA-seq (159 samples), Affymetrix SNP 6.0 copy number arrays, DNA methylation arrays
  • Methods: whole-exome-seq, whole-genome-seq, rna-seq, affymetrix-snp6, GISTIC, MutSig

Key findings

  • Mean somatic mutation rate of 8.1 mutations/Mb (median 8.4/Mb), higher than all other TCGA tumor types at the time (p < 2.2e-16).
  • Mean of 360 exonic mutations, 323 copy number segments, and 165 genomic rearrangements per tumor.
  • 10 significantly mutated genes (FDR q < 0.1): TP53, CDKN2A, PTEN, PIK3CA, KEAP1, KMT2D (MLL2), HLA-A, NFE2L2, NOTCH1, RB1.
  • 12 additional significantly mutated genes from COSMIC-restricted analysis: AMER1 (FAM123B/WTX), HRAS, FBXW7, SMARCA4, NF1, SMAD4, EGFR, APC, TSC1, BRAF, TNFAIP3, CREBBP.
  • NFE2L2/KEAP1/CUL3 pathway altered in 34% of tumors; mutations in NFE2L2 concentrated in KEAP1-interaction motifs (DLG/ETGE).
  • Squamous differentiation pathway altered in 44%: overexpression/amplification of SOX2 and TP63, loss-of-function mutations in NOTCH1, NOTCH2, and ASCL4.
  • PI3K/AKT pathway altered in 47%: PIK3CA, PTEN, or AKT3.
  • CDKN2A/RB1 pathway altered in 72%, through methylation (21%), mutation (18%), exon 1-beta skipping (4%), and homozygous deletion (29%).
  • Four gene expression subtypes identified: classical (36%), basal (25%), secretory (24%), primitive (15%).
  • Chromosome 3q selectively amplified in LUSC vs. lung adenocarcinoma (p < 1e-15).
  • EGFR/KRAS mutations common in lung adenocarcinoma are essentially absent in LUSC.
  • 64% of tumors harbored a potentially targetable somatic alteration.
  • No recurrent in-frame fusion proteins were identified despite a high rearrangement burden.

Genes & alterations

Gene Alteration Frequency / Detail
TP53 Mutation 81% (automated); up to 90% with manual review
CDKN2A Deletion, mutation, methylation, exon skipping 72% (combined pathway inactivation)
PIK3CA Mutation, amplification Part of 47% PI3K pathway alteration
PTEN Mutation, deletion Part of 47% PI3K pathway alteration
NFE2L2 Activating mutation (DLG/ETGE motifs) Part of 34% oxidative stress pathway
KEAP1 Loss-of-function mutation Mutually exclusive with NFE2L2 mutations
CUL3 Deletion, mutation Part of NFE2L2/KEAP1 pathway
NOTCH1 Truncating mutations (8/17 loss-of-function) Part of 44% squamous differentiation
SOX2 Amplification, overexpression 3q26 amplicon; squamous differentiation
TP63 Amplification, deltaN overexpression 3q26 amplicon; oncogenic deltaN isoform
FGFR1 Amplification Therapeutic target candidate
EGFR Amplification (7%), L861Q mutation (2 cases) No L858R or exon 19 deletions
HLA-A Nonsense/splice site (7/8 loss-of-function) Novel; immune evasion
RB1 Mutation Primitive subtype association
DDR2 Mutation Previously nominated therapeutic target
KMT2D Mutation Significantly mutated (FDR < 0.1)
NF1 Mutation, deletion, rearrangement Basal subtype association
MDM2 Amplification Novel SCNA region
CDK6 Amplification RB1 pathway alternative

Clinical implications

  • 64% of LUSC tumors contain a potentially targetable alteration in a kinase, PI3K subunit, or RTK pathway gene, suggesting opportunity for targeted therapy trials.
  • EGFR L861Q mutations (2 cases) confer sensitivity to erlotinib and gefitinib, but canonical adenocarcinoma EGFR mutations are absent.
  • FGFR1 amplification is a candidate therapeutic target; FGFR family members are commonly mutated/amplified.
  • Inactivating HLA-A mutations suggest a role for genotypic selection of patients for immunotherapy (anti-PD1, anti-CTLA4).
  • PI3K pathway alterations (47%) are mutually exclusive with EGFR alterations, pointing to non-overlapping targetable subgroups.
  • Expression subtypes correlate with specific pathway alterations, potentially informing subtype-specific therapeutic strategies.

Limitations & open questions

  • Functional dependence of LUSC tumors on the identified alterations was not experimentally validated in this study.
  • Median follow-up was only 15.8 months, limiting survival analyses.
  • The cohort is predominantly North American with 96% tobacco-use history; generalizability to never-smoker LUSC or non-Western cohorts is uncertain.
  • No recurrent actionable gene fusions were found despite high rearrangement burden; the clinical significance of passenger rearrangements remains unclear.
  • Whether expression subtypes (classical, basal, secretory, primitive) predict therapeutic response requires prospective validation.

Citations from this paper used in the wiki

  • “We identified 10 genes with a false discovery rate (FDR) q value <0.1: TP53, CDKN2A, PTEN, PIK3CA, KEAP1, MLL2, HLA-A, NFE2L2, NOTCH1 and RB1” (Page 3)
  • “TP53 mutation was observed in 81% of samples by automated analysis; visual review of sequencing reads identified an additional 9% of samples with potential mutations” (Page 3-4)
  • “We observed mutations and copy number alterations of NFE2L2 and KEAP1 and/or deletion or mutation of CUL3 in 34% of cases” (Page 4)
  • “alterations in genes with known roles in squamous cell differentiation in 44% of samples” (Page 5)
  • “one of three components of the PI3K/Akt pathway (PIK3CA, PTEN or AKT3) was altered in 47% of tumors” (Page 7)
  • “CDKN2A…is inactivated in 72% of cases of lung SqCC” (Page 6)
  • “we identified 114 cases with somatic alteration of a potentially targetable gene (64%)” (Page 7)
  • “Mutations in HLA-A were also almost exclusively nonsense or splice site events (7 of 8)” (Page 4)
  • “amplifications of EGFR were found in 7% of cases as were two instances of the L861Q EGFR mutation, which confers sensitivity to erlotinib and gefitinib” (Page 7)

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