Journal
NATURE
Volume 511, Issue 7511, Pages 543-550Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13385
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Funding
- NIH [U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA137153, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866]
- The NIH [U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079, U54 HG003273]
- Div Of Information & Intelligent Systems
- Direct For Computer & Info Scie & Enginr [1054631] Funding Source: National Science Foundation
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Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen(mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
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