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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.
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.
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.
Shares Copy number alteration (CNA), EGFR exon 19 deletion, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Nature Genetics.
Shares Field cancerisation, Mutagenesis & mutational signatures, Mutational signature, Clonal evolution & minimal residual disease.
Shares Nature Genetics, Receptor tyrosine kinase activation, TP53, EGFR.
Shares Mutagenesis & mutational signatures, Mutational signature, Tumour mutational burden (TMB), Whole-exome & whole-genome sequencing.
Shares Mutagenesis & mutational signatures, Mutational signature, Clonal evolution & minimal residual disease, Whole-exome & whole-genome sequencing.
Shares HER2 (ERBB2) activating mutation, Driver mutation, MET, ALK.
Shares Nature Genetics, Clonal evolution & minimal residual disease, Driver mutation, Whole-exome & whole-genome sequencing.
Shares Driver mutation, MET, ALK, Receptor tyrosine kinase activation.