{"entity":{"id":"paper-zhang-lung-cancer-never-smokers-sherlock-nat-genet-2021","kind":"paper","name":"Genomic and evolutionary classification of lung cancer in never smokers","aka":[],"tldr":"Reading the whole genomes of 232 lung cancers in people who never smoked found no fingerprint of tobacco, even where secondhand smoke was recorded, and split the disease into three kinds, one of which grows so slowly that its first driver mutation appears to date back decades.","summary":"High-coverage whole-genome sequencing of 232 lung cancers in never smokers identified three subtypes defined by copy-number aberration. The dominant subtype, piano, which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline androgen receptor variants and stem-cell-like properties, including low mutational burden, high intratumour heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumour diagnosis. The other two subtypes are characterised by specific amplifications with EGFR mutations (mezzo-forte) and by whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with recorded exposure to secondhand tobacco smoke. Genes in the receptor tyrosine kinase and RAS pathway had distinct effects on survival, and five genomic alterations independently doubled mortality.","asOf":"2026-09-25","links":[{"label":"Zhang et al., Nat Genet 2021: genomic and evolutionary classification of 232 lung cancers in never smokers (Sherlock-Lung)","url":"https://doi.org/10.1038/s41588-021-00920-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34493867/"},{"label":"cBioPortal study lung_nci_2022 (Sherlock-Lung, NCI, Nat Genet 2021; 232 whole genomes of lung cancer in never smokers)","url":"https://www.cbioportal.org/study/summary?id=lung_nci_2022"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["wes-wgs","low-dose-ct-screening"],"targets":["egfr","kras","tp53","alk","her2","met"],"drugs":[],"companies":[],"institutions":[],"pathways":["mutagenesis-signatures","chromosomal-instability","clonal-evolution","rtk-activation","field-cancerisation"],"terms":["mutational-signature","driver-mutation","tmb","copy-number-variation-term"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":2021,"doi":"10.1038/s41588-021-00920-0","pmid":"34493867","authors":"Zhang T, Joubert P, Ansari-Pour N, et al.","paperType":"basic","findings":["No strong tobacco signature in never-smoker lung cancer, including in cases with secondhand exposure.","Three copy-number subtypes: piano, mezzo-forte and forte.","The piano subtype is slow growing, with driver progenitor cells dating back many years before diagnosis.","Five genomic alterations independently doubled mortality."],"whatItMeans":"It establishes lung cancer in never smokers as a separate disease with its own natural history, and the decades-long lead time of the slow subtype is a direct argument for screening people who would never qualify on smoking history.","caveats":["Secondhand smoke exposure was recorded by questionnaire, which is imprecise.","232 genomes from several countries, so subtype frequencies may not generalise.","The timing of the first driver is inferred from molecular clocks rather than observed."],"changedPractice":false,"participants":232},"route":"/key-papers/paper-zhang-lung-cancer-never-smokers-sherlock-nat-genet-2021/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"low-dose-ct-screening","kind":"technology","name":"Low-dose CT lung screening","route":"/technologies/low-dose-ct-screening/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"field-cancerisation","kind":"pathway","name":"Field cancerisation","route":"/pathways/field-cancerisation/"},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"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":"egfr-mutation-subtypes","kind":"term","name":"EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M)","route":"/terms/egfr-mutation-subtypes/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"journal":[{"id":"nature-genetics","kind":"journal","name":"Nature Genetics","route":"/journals/nature-genetics/"}],"biomarker":[{"id":"egfr-exon-19-deletion","kind":"biomarker","name":"EGFR exon 19 deletion","route":"/biomarkers/egfr-exon-19-deletion/"},{"id":"her2-mutation","kind":"biomarker","name":"HER2 (ERBB2) activating mutation","route":"/biomarkers/her2-mutation/"}]}}