Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers1,2 and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies3-5. Here we use data from the Sherlock-Lung study to evaluate mutagenic exposures in LCINS by examining the cancer genomes of 871 treatment-naive individuals with lung cancer who had never smoked, from 28 geographical locations. KRAS mutations were 3.8 times more common in adenocarcinomas of never smokers from North America and Europe than in those from East Asia, whereas a higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas of never smokers from East Asia. Signature SBS40a, with unknown cause6, contributed the largest proportion of single base substitutions in adenocarcinomas, and was enriched in cases with EGFR mutations. Signature SBS22a, which is associated with exposure to aristolochic acid7,8, was observed almost exclusively in patients from Taiwan. Exposure to secondhand smoke was not associated with individual driver mutations or mutational signatures. By contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations and shorter telomeres. They also exhibited an increase in most types of mutations, including a 3.9-fold increase in signature SBS4, which has previously been linked with tobacco smoking9, and a 76% increase in the clock-like10 signature SBS5. A positive dose-response effect was observed with air-pollution levels, correlating with both a decrease in telomere length and an increase in somatic mutations, mainly attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

Ben May Department for Cancer Research University of Chicago Chicago IL USA

Biobanco IBSP CV FISABIO Valencia Spain

Cancer Evolution and Genome Instability Laboratory Francis Crick Institute London UK

Cancer Genomics Research Laboratory Leidos Biomedical Research Frederick National Laboratory for Cancer Research Frederick MD USA

Cancer Research UK Lung Cancer Centre of Excellence University College London Cancer Institute London UK

Clinic of Pulmonology Clinical Center of Serbia Belgrade Serbia

Department of Bioengineering University of California San Diego La Jolla CA USA

Department of Cancer Epidemiology and Primary Prevention Maria Skłodowska Curie National Research Institute of Oncology Warsaw Poland

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA

Department of Clinical Epidemiology N N Blokhin National Medical Research Centre of Oncology Moscow Russia

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Łódź Poland

Department of Environmental Health Harvard T H Chan School of Public Health Boston MA USA

Department of Health Informatics Graduate School of Informatics Middle East Technical University Ankara Turkey

Department of Human Genetics University of Chicago Chicago IL USA

Department of Mathematics Harvard University Cambridge MA USA

Department of Medicine Massachusetts General Hospital Boston MA USA

Department of Occupational Health and Toxicology National Center for Environmental Risk Monitoring National Institute of Public Health Bucharest Romania

Department of Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Organismic and Evolutionary Biology Harvard University Cambridge MA USA

Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pathology Brigham and Women's Hospital Boston MA USA

Department of Pathology Centre Hospitalier de l'Université de Montréal Montreal Quebec Canada

Department of Pathology University of Hong Kong Hong Kong China

Department of Pathology Yale School of Medicine New Haven CT USA

Digital Genomics Group Cancer Genomics Program Spanish National Cancer Research Center Madrid Spain

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Division of Pulmonary and Critical Care Medicine Mayo Clinic Rochester MN USA

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Genomic Epidemiology Branch International Agency for Research on Cancer Lyon France

IHU RespirERA Biobank BB 0033 0025 Côte d'Azur University Nice France

Institut Universitaire de Cardiologie et de Pneumologie de Québec Université Laval Quebec City Quebec Canada

Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan

Institute of Public Health and Preventive Medicine 2nd Faculty of Medicine Charles University Prague Czech Republic

International Organization for Cancer Prevention and Research Belgrade Serbia

Manchester Cancer Research Centre University of Manchester Manchester UK

Manchester NIHR Biomedical Research Centre Manchester UK

Moores Cancer Center University of California San Diego La Jolla CA USA

National Institute of Cancer Research National Health Research Institutes Zhunan Taiwan

Princess Margaret Cancer Center University of Toronto Toronto Ontario Canada

Queen Mary Hospital University of Hong Kong Hong Kong China

Red Valenciana de Biobancos FISABIO Valencia Spain

Sanford Stem Cell Institute University of California San Diego La Jolla CA USA

Sylvester Comprehensive Cancer Center Department of Medicine University of Miami Miller School of Medicine Miami FL USA

Thoracic Surgery Roswell Park Comprehensive Cancer Center Buffalo NY USA

University of Chicago Medicine Comprehensive Cancer Center University of Chicago Chicago IL USA

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