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

  1. Author:
    Díaz-Gay, Marcos [ORCID]
    Zhang, Tongwu [ORCID]
    Hoang, Phuc H [ORCID]
    Leduc, Charles
    Baine, Marina K
    Travis, William D
    Sholl, Lynette M [ORCID]
    Joubert, Philippe
    Khandekar, Azhar
    Zhao, Wei [ORCID]
    Steele, Christopher D
    Otlu, Burçak
    Nandi, Shuvro P [ORCID]
    Vangara, Raviteja [ORCID]
    Bergstrom, Erik N
    Kazachkova, Mariya
    Pich, Oriol [ORCID]
    Swanton, Charles [ORCID]
    Hsiung, Chao Agnes
    Chang, I-Shou
    Wong, Maria Pik
    Leung, Kin Chung
    Sang, Jian
    McElderry, John P
    Hartman, Caleb [ORCID]
    Colón-Matos, Frank J
    Miraftab, Mona
    Saha, Monjoy
    Lee, Olivia W [ORCID]
    Jones,Kristine [ORCID]
    Gallego-García, Pilar [ORCID]
    Yang, Yang [ORCID]
    Zhong, Xiaoming
    Edell, Eric S
    Santamaría, Jacobo Martínez [ORCID]
    Schabath, Matthew B [ORCID]
    Yendamuri, Sai S
    Manczuk, Marta [ORCID]
    Lissowska, Jolanta [ORCID]
    Swiatkowska, Beata [ORCID]
    Mukeria, Anush
    Shangina, Oxana
    Zaridze, David
    Holcatova, Ivana
    Mates, Dana
    Milosavljevic, Sasa
    Kontic, Millica
    Bossé, Yohan [ORCID]
    Rothberg, Bonnie E Gould [ORCID]
    Christiani, David C [ORCID]
    Gaborieau, Valerie
    Brennan, Paul
    Liu, Geoffrey
    Hofman, Paul [ORCID]
    Yang, Lixing
    Nowak, Martin A
    Shi, Jianxin [ORCID]
    Rothman, Nathaniel
    Wedge, David C [ORCID]
    Homer, Robert [ORCID]
    Yang, Soo-Ryum
    Pesatori, Angela C [ORCID]
    Consonni, Dario [ORCID]
    Lan, Qing [ORCID]
    Zhu, Bin [ORCID]
    Chanock, Stephen J [ORCID]
    Choi, Jiyeon [ORCID]
    Alexandrov, Ludmil B [ORCID]
    Landi, Maria Teresa [ORCID]

  2. Author Address

    1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. 2Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. 3Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. 4Digital Genomics Group, Cancer Genomics Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 6Department of Pathology, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. 7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 8Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. 9Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Quebec City, Quebec, Canada. 10Department of Health Informatics, Graduate School of Informatics, Middle East Technical University, Ankara, Turkey. 11Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, UK. 12Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. 13Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. 14National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan. 15Queen Mary Hospital, University of Hong Kong, Hong Kong, China. 16Department of Pathology, University of Hong Kong, Hong Kong, China. 17Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. 18Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. 19Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA. 20Biobanco IBSP-CV FISABIO, Valencia, Spain. 21Red Valenciana de Biobancos FISABIO, Valencia, Spain. 22Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 23Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 24Department of Cancer Epidemiology and Primary Prevention, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 25Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lódz, Poland. 26Department of Clinical Epidemiology, N.N. Blokhin National Medical Research Centre of Oncology, Moscow, Russia. 27Institute of Public Health and Preventive Medicine, Second Faculty of Medicine, Charles University, Prague, Czech Republic. 28Department of Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. 29Department of Occupational Health and Toxicology, National Center for Environmental Risk Monitoring, National Institute of Public Health, Bucharest, Romania. 30International Organization for Cancer Prevention and Research (IOCPR), Belgrade, Serbia. 31Clinic of Pulmonology, Clinical Center of Serbia, Belgrade, Serbia. 32Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. 33Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 34Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. 35Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France. 36Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada. 37IHU RespirERA, Biobank-BB-0033-0025, Côte d'Azur University, Nice, France. 38Department of Human Genetics, University of Chicago, Chicago, IL, USA. 39University of Chicago Medicine Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA. 40Department of Mathematics, Harvard University, Cambridge, MA, USA. 41Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. 42Manchester Cancer Research Centre, University of Manchester, Manchester, UK. 43Manchester NIHR Biomedical Research Centre, Manchester, UK. 44Department of Pathology, Yale School of Medicine, New Haven, CT, USA. 45Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. 46Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 47Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. 48Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. 49Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. 50Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, USA. L2alexandrov@health.ucsd.edu. 51Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. landim@nih.gov.
    1. Year: 2025
    2. Date: Jul 02
    3. Epub Date: 2025 07 02
  2. Journal: Nature
  4. Type of Article: Article
  1. Abstract:

    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. © 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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  2. DOI: 10.1038/s41586-025-09219-0
  3. PMID: 40604281
  4. PII : 10.1038/s41586-025-09219-0

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  1. Fiscal Year: FY2024-2025
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