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Reading 230 surgically removed lung adenocarcinomas on every available platform produced the reference map of the disease, found three new driver genes, and showed that a tenth of tumours with no obvious oncogene were driven by alterations nobody had counted as drivers before.
Molecular profiling of 230 resected lung adenocarcinomas combined messenger RNA, microRNA and DNA sequencing with copy number, methylation and proteomic analyses. Somatic mutation rates were high, a mean of 8.9 mutations per megabase. Eighteen genes were significantly mutated, including activating RIT1 mutations and newly described loss-of-function MGA mutations that were mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in women and RBM10 mutations in men. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples that otherwise lacked an activated oncogene, arguing that they are drivers in those tumours. Matched DNA and messenger RNA revealed splicing alterations driven by somatic genomic change, including exon 14 skipping in MET messenger RNA in 4% of cases. MAPK and PI3K pathway activity measured at the protein level was explained by known mutations in only a fraction of cases.
It is the reference table the field still argues against, and it made two practical points that outlived it: a tumour with no driver on a standard panel usually has one that the panel did not look for, and pathway activity measured on protein does not follow from the mutation list.
Shares Matthew Meyerson, Somatic mutations from exome and genome sequencing (WXS, WGS), NF1 (neurofibromin), Broad Institute of MIT and Harvard.
Shares KEAP1, STK11, Non-small cell lung cancer (KEGG map), Driver mutation.
Shares NKX2-1, KEAP1-NRF2 antioxidant pathway, KEAP1, STK11.
Shares KEAP1, STK11, Non-small cell lung cancer (KEGG map), Driver mutation.
Shares KEAP1-NRF2 antioxidant pathway, KEAP1, Broad Institute of MIT and Harvard, Non-small cell lung cancer (KEGG map).
Shares Somatic mutations from exome and genome sequencing (WXS, WGS), Broad Institute of MIT and Harvard, Nature, DNA methylation profiling.
Shares Driver mutation, MET, Receptor tyrosine kinase activation, Whole-exome & whole-genome sequencing.
Shares KEAP1-NRF2 antioxidant pathway, KEAP1, STK11, TP53.