{"entity":{"id":"paper-tcga-lung-squamous-nature-2012","kind":"paper","name":"Comprehensive genomic characterization of squamous cell lung cancers","aka":[],"tldr":"The first complete genomic reading of 178 squamous lung cancers found a chaotic genome with almost universal loss of the p53 gene, and identified a possible drug target in most tumours in a cancer that until then had none.","summary":"One hundred and seventy-eight lung squamous cell carcinomas were profiled across platforms. The tumour type is characterised by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements and 323 segments of copy-number alteration per tumour. Recurrent mutations were found in 11 genes, including TP53 in nearly all specimens. Previously unreported loss-of-function mutations were seen in the class I gene HLA-A. Significantly altered pathways included NFE2L2 and KEAP1 in 34% of tumours, squamous differentiation genes in 44%, phosphatidylinositol-3-kinase pathway genes in 47%, and CDKN2A and RB1 in 72%. A potential therapeutic target was identified in most tumours.","asOf":"2026-09-25","links":[{"label":"Cancer Genome Atlas Research Network, Nature 2012: comprehensive genomic characterisation of 178 squamous cell lung cancers","url":"https://doi.org/10.1038/nature11404"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22960745/"},{"label":"cBioPortal study lusc_tcga_pub (TCGA, Nature 2012; the 178 squamous cell lung cancers of the landmark paper)","url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_pub"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["wes-wgs","rna-seq","methylation-profiling"],"targets":["tp53","cdkn2a","rb1","nfe2l2","keap1","cul3","pik3ca","pten","sox2","tp63","fgfr1","hla-a","notch1"],"drugs":[],"companies":[],"institutions":["broad-institute"],"pathways":["nsclc-signalling","keap1-nrf2","p53-cell-cycle","pi3k-akt-mtor","chromosomal-instability","antigen-presentation-immunoediting"],"terms":["gene-amplification","copy-number-variation-term","driver-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2012,"doi":"10.1038/nature11404","pmid":"22960745","authors":"Cancer Genome Atlas Research Network.","paperType":"basic","findings":["TP53 mutated in nearly all specimens; a mean of 360 exonic mutations and 323 copy-number segments per tumour.","NFE2L2 and KEAP1 pathway altered in 34%, squamous differentiation genes in 44%, PI3K pathway in 47%, CDKN2A and RB1 in 72%.","Loss-of-function mutations in HLA-A, a route to immune escape.","A candidate therapeutic target present in most tumours."],"whatItMeans":"It explained why squamous lung cancer has no equivalent of an EGFR inhibitor: its commonest alterations are a transcription factor amplicon, a tumour suppressor deletion and an antioxidant switch, none of which is a drug target in the way a mutant kinase is.","caveats":["The candidate targets identified here, including FGFR1 and the PI3K pathway, have largely failed in trials since.","A resected cohort, so stage IV biology is not represented.","178 tumours, so rarer events are missed."],"changedPractice":false,"participants":178},"route":"/key-papers/paper-tcga-lung-squamous-nature-2012/","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":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"cul3","kind":"target","name":"CUL3","route":"/targets/cul3/"},{"id":"fgfr1","kind":"target","name":"FGFR1","route":"/targets/fgfr1/"},{"id":"hla-a","kind":"target","name":"HLA-A","route":"/targets/hla-a/"},{"id":"keap1","kind":"target","name":"KEAP1","route":"/targets/keap1/"},{"id":"nfe2l2","kind":"target","name":"NFE2L2","route":"/targets/nfe2l2/"},{"id":"notch1","kind":"target","name":"NOTCH1","route":"/targets/notch1/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"sox2","kind":"target","name":"SOX2","route":"/targets/sox2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"tp63","kind":"target","name":"TP63","route":"/targets/tp63/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"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":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"}],"term":[{"id":"copy-number-variation-term","kind":"term","name":"Copy number alteration (CNA)","route":"/terms/copy-number-variation-term/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"gene-amplification","kind":"term","name":"Gene amplification and copy-number change","route":"/terms/gene-amplification/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}