{"entity":{"id":"paper-tcga-lung-adenocarcinoma-nature-2014","kind":"paper","name":"Comprehensive molecular profiling of lung adenocarcinoma","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-25","links":[{"label":"Cancer Genome Atlas Research Network, Nature 2014: comprehensive molecular profiling of 230 resected lung adenocarcinomas","url":"https://doi.org/10.1038/nature13385"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25079552/"},{"label":"cBioPortal study luad_tcga_pub (TCGA, Nature 2014; the 230 resected lung adenocarcinomas of the landmark paper)","url":"https://www.cbioportal.org/study/summary?id=luad_tcga_pub"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["wes-wgs","rna-seq","methylation-profiling"],"targets":["egfr","kras","tp53","stk11","keap1","met","nf1","rbm10","rit1","mga","her2","nkx2-1"],"drugs":[],"companies":[],"institutions":["broad-institute"],"pathways":["nsclc-signalling","ras-mapk","rtk-activation","pi3k-akt-mtor","keap1-nrf2"],"terms":["driver-mutation","met-exon-14-skipping","somatic-mutations-wxs-wgs"],"trials":[],"people":["matthew-meyerson"],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2014,"doi":"10.1038/nature13385","pmid":"25079552","authors":"Cancer Genome Atlas Research Network.","paperType":"basic","findings":["Mean somatic mutation rate 8.9 per megabase, among the highest of any cancer.","Eighteen significantly mutated genes, adding RIT1 and MGA to the driver list.","NF1, MET, ERBB2 and RIT1 aberrations in 13% of cases, enriched where no other oncogene was activated.","MET exon 14 skipping read directly in messenger RNA in 4% of tumours."],"whatItMeans":"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.","caveats":["A surgical, mostly early-stage, mostly smoker cohort, so the driver frequencies do not match those of a metastatic clinic.","Fusion detection was limited by the sequencing used, so ALK, ROS1 and RET rates read low.","230 tumours is too few to find drivers below about 2%."],"changedPractice":false,"participants":230},"route":"/key-papers/paper-tcga-lung-adenocarcinoma-nature-2014/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"keap1","kind":"target","name":"KEAP1","route":"/targets/keap1/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"},{"id":"mga","kind":"target","name":"MGA","route":"/targets/mga/"},{"id":"nf1","kind":"target","name":"NF1 (neurofibromin)","route":"/targets/nf1/"},{"id":"nkx2-1","kind":"target","name":"NKX2-1","route":"/targets/nkx2-1/"},{"id":"rbm10","kind":"target","name":"RBM10","route":"/targets/rbm10/"},{"id":"rit1","kind":"target","name":"RIT1","route":"/targets/rit1/"},{"id":"stk11","kind":"target","name":"STK11","route":"/targets/stk11/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"}],"pathway":[{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","route":"/pathways/keap1-nrf2/"},{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"met-exon-14-skipping","kind":"term","name":"MET exon 14 skipping mutation","route":"/terms/met-exon-14-skipping/"},{"id":"somatic-mutations-wxs-wgs","kind":"term","name":"Somatic mutations from exome and genome sequencing (WXS, WGS)","route":"/terms/somatic-mutations-wxs-wgs/"}],"person":[{"id":"matthew-meyerson","kind":"person","name":"Matthew Meyerson","route":"/people/matthew-meyerson/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}],"biomarker":[{"id":"met-ex14","kind":"biomarker","name":"MET exon 14 skipping mutation","route":"/biomarkers/met-ex14/"}]}}