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Healthy lungs already carry cancer-causing mutations. This study argues that fine particles in polluted air do not create the mutation but wake it up, which is why lung cancer happens in people who never smoked.
Hill, Lim, Weeden and colleagues from the TRACERx consortium and the Francis Crick Institute, with Swanton as senior author, proposed that particulate matter of 2.5 micrometres or less promotes lung cancer by acting on cells that already carry oncogenic mutations in otherwise healthy lung tissue, rather than by causing those mutations.
The paper combines epidemiology across four within-country cohorts, functional mouse models and ultradeep sequencing of histologically normal lung. It revives the two-step initiation-and-promotion model of tumorigenesis proposed more than seventy years earlier, and gives it a molecular mechanism: an influx of macrophages, release of interleukin-1 beta and a progenitor-like state in EGFR-mutant alveolar type II cells.
It reframes air quality as cancer policy rather than respiratory policy, and it explains the shape of lung cancer in never-smokers: the mutations are common and mostly silent, and what differs is whether something inflames the tissue enough to let one of them grow.
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.
Why targeting a clonal driver works and targeting a subclonal one usually does not, and why a single-site biopsy can mislead. Chromosomal instability is now a candidate prognostic marker in its own right.
Shares Tracking the evolution of non-small-cell lung cancer, Charles Swanton, The Francis Crick Institute, Nature and the tag lung-evidence.
Shares Adenocarcinoma of the lung, Driver mutation, Nature, 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 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, Prevention we already have is not deployed, The hardest cancers are found late, Lung cancer (all types) and the tag lung-evidence.
Shares Treat lung cancer in never-smokers as its own disease, with its own detection programme, 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, Prevention we already have is not deployed, The hardest cancers are found late 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, EGFR 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, EGFR 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, EGFR and the tag lung-evidence.
Shares 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, Prevention we already have is not deployed, The hardest cancers are found late, Lung cancer (all types) and the tag lung-evidence.