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The mutagenic forces shaping the genomes of lung cancer in never smokers

Díaz-Gay, M.
; 
Zhang, T.
; 
Hoang, P. H.
; 
Leduc, C.
; 
Baine, M. K.
; 
Travis, W. D.
; 
Sholl, L. M.
; 
Joubert, P.
; 
Khandekar, A.
; 
Zhao, W.
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Abstract
Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers(1,2) and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies(3-5). 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 cause(6), 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 acid(7,8), 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 smoking(9), and a 76% increase in the clock-like(10) 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.
Authors
Díaz-Gay, M.
Zhang, T.
Hoang, P. H.
Leduc, C.
Baine, M. K.
Travis, W. D.
Sholl, L. M.
Joubert, P.
Khandekar, A.
Zhao, W.
Steele, C. D.
Otlu, B.
Nandi, S. P.
Vangara, R.
Bergstrom, E. N.
Kazachkova, M.
Pich, O.
Swanton, C.
Hsiung, C. A.
Chang, I. S.
Wong, M. P.
Leung, K. C.
Sang, J.
McElderry, J. P.
Hartman, C.
Colón-Matos, F. J.
Miraftab, M.
Saha, M.
Lee, O. W.
Jones, K. M.
Gallego-García, P.
Yang, Y.
Zhong, X.
Edell, E. S.
Santamaría, J. M.
Schabath, M. B.
Yendamuri, S. S.
Manczuk, M.
Lissowska, J.
Świątkowska, B.
Mukeria, A.
Shangina, O.
Zaridze, D.
Holcatova, I.
Mates, D.
Milosavljevic, S.
Kontic, M.
Bossé, Y.
Rothberg, B. E. G.
Christiani, D. C.
Gaborieau, V.
Brennan, P.
Liu, G.
Hofman, P.
Yang, L.
Nowak, M. A.
Shi, J.
Rothman, N.
Wedge, D. C.
Homer, R.
Yang, S. R.
Pesatori, A. C.
Consonni, D.
Lan, Q.
Zhu, B.
Chanock, S. J.
Choi, J.
Alexandrov, L. B.
Landi, M. T.
Affiliation
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Digital Genomics Group, Cancer Genomics Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Department of Pathology, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. 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. Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Quebec City, Quebec, Canada. Department of Health Informatics, Graduate School of Informatics, Middle East Technical University, Ankara, Turkey. Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan. Queen Mary Hospital, University of Hong Kong, Hong Kong, China. Department of Pathology, University of Hong Kong, Hong Kong, China. Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA. Biobanco IBSP-CV FISABIO, Valencia, Spain. Red Valenciana de Biobancos FISABIO, Valencia, Spain. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Department of Cancer Epidemiology and Primary Prevention, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland. Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Łódź, Poland. Department of Clinical Epidemiology, N.N. Blokhin National Medical Research Centre of Oncology, Moscow, Russia. Institute of Public Health and Preventive Medicine, Second Faculty of Medicine, Charles University, Prague, Czech Republic. Department of Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. Department of Occupational Health and Toxicology, National Center for Environmental Risk Monitoring, National Institute of Public Health, Bucharest, Romania. International Organization for Cancer Prevention and Research (IOCPR), Belgrade, Serbia. Clinic of Pulmonology, Clinical Center of Serbia, Belgrade, Serbia. Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France. Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada. IHU RespirERA, Biobank-BB-0033-0025, Côte d'Azur University, Nice, France. Department of Human Genetics, University of Chicago, Chicago, IL, USA. University of Chicago Medicine Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA. Department of Mathematics, Harvard University, Cambridge, MA, USA. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. Manchester Cancer Research Centre, University of Manchester, Manchester, UK. Manchester NIHR Biomedical Research Centre, Manchester, UK. Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. landim@nih.gov.
Description
Date
2025
Publisher
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All Paterson Institute for Cancer Research
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Article
Citation
Díaz-Gay M, Zhang T, Hoang PH, Leduc C, Baine MK, Travis WD, et al. The mutagenic forces shaping the genomes of lung cancer in never smokers. Nature. 2025 Aug;644(8075):133-44. PubMed PMID: 40604281. Epub 2025/07/03. eng.
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https://christie.openrepository.com/handle/10541/628176
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