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The Sherlock-Lung study sequenced 232 lung cancers from people who never smoked and found three distinct types, none of them carrying the tobacco damage signature. One type appears to begin decades before it is diagnosed.
Zhang, Joubert, Ansari-Pour and colleagues, with Landi as senior author, performed high-coverage whole-genome sequencing of 232 lung cancers in never smokers and defined three subtypes by copy-number aberration, named piano, mezzo-forte and forte.
The dominant piano subtype is rare in smokers' lung cancer: low mutational burden, high intratumour heterogeneity, long telomeres, frequent KRAS mutations, stem cell-like properties and slow growth, with driver progenitor cells datable to many years before diagnosis. Mezzo-forte carries specific amplifications and EGFR mutations; forte is defined by whole-genome doubling. No strong tobacco smoking signatures were detected, even in cases with secondhand smoke exposure.
Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find.
Shares TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, Clonal evolution & minimal residual disease, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Tumour heterogeneity and clonal evolution and the tag lung-evidence.
Shares EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Tumour heterogeneity and clonal evolution and the tag lung-evidence.
Shares Adenocarcinoma of the lung, Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, ALK and the tag lung-evidence.
Shares Copy number alteration (CNA), Chromosomal instability & aneuploidy, Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch and the tag lung-evidence.
Shares TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, Clonal evolution & minimal residual disease, MET, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch and the tag lung-evidence.
Shares Low-dose CT lung screening, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, The hardest cancers are found late, National Cancer Institute (NIH) and the tag lung-evidence.
Shares Treat lung cancer in never-smokers as its own disease, with its own detection programme, Low-dose CT lung screening, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, The hardest cancers are found late and the tag lung-evidence.
Shares Driver mutation, MET, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Rare and paediatric cancers without markets and the tag lung-evidence.