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

Marcos Díaz-Gay^#^{1

2

3

4}, Tongwu Zhang^#⁵, Phuc H Hoang⁵, Charles Leduc⁶, Marina K Baine⁷, William D Travis⁷, Lynette M Sholl⁸, Philippe Joubert⁹, Azhar Khandekar^{1

2

3

5}, Wei Zhao⁵, Christopher D Steele^{1

2

3}, Burçak Otlu^{1

2

3

10}, Shuvro P Nandi^{1

2

3}, Raviteja Vangara^{1

2

3}, Erik N Bergstrom^{1

2

3}, Mariya Kazachkova^{1

2

3}, Oriol Pich¹¹, Charles Swanton^{11

12}, Chao Agnes Hsiung¹³, I-Shou Chang¹⁴, Maria Pik Wong¹⁵, Kin Chung Leung¹⁶, Jian Sang⁵, John P McElderry⁵, Caleb Hartman⁵, Frank J Colón-Matos⁵, Mona Miraftab⁵, Monjoy Saha⁵, Olivia W Lee⁵, Kristine M Jones^{5

17}, Pilar Gallego-García⁴, Yang Yang¹⁸, Xiaoming Zhong¹⁸, Eric S Edell¹⁹, Jacobo Martínez Santamaría^{20

21}, Matthew B Schabath²², Sai S Yendamuri²³, Marta Manczuk²⁴, Jolanta Lissowska²⁴, Beata Świątkowska²⁵, Anush Mukeria²⁶, Oxana Shangina²⁶, David Zaridze²⁶, Ivana Holcatova^{27

28}, Dana Mates²⁹, Sasa Milosavljevic³⁰, Millica Kontic³¹, Yohan Bossé⁹, Bonnie E Gould Rothberg³², David C Christiani^{33

34}, Valerie Gaborieau³⁵, Paul Brennan³⁵, Geoffrey Liu³⁶, Paul Hofman³⁷, Lixing Yang^{18

38

39}, Martin A Nowak^{40

41}, Jianxin Shi⁵, Nathaniel Rothman⁵, David C Wedge^{42

43}, Robert Homer⁴⁴, Soo-Ryum Yang⁷, Angela C Pesatori^{45

46}, Dario Consonni⁴⁶, Qing Lan⁵, Bin Zhu⁵, Stephen J Chanock⁵, Jiyeon Choi⁵, Ludmil B Alexandrov^{47

48

49

50}, Maria Teresa Landi⁵¹

Affiliations

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

^# Contributed equally.

PMID: 40604281
DOI: 10.1038/s41586-025-09219-0

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

Marcos Díaz-Gay et al. Nature. 2025 Aug.

. 2025 Aug;644(8075):133-144.

doi: 10.1038/s41586-025-09219-0. Epub 2025 Jul 2.

Authors

Affiliations

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

^# Contributed equally.

PMID: 40604281
DOI: 10.1038/s41586-025-09219-0

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 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 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 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.

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Conflict of interest statement

Competing interests: L.B.A. is a co-founder, CSO, scientific advisory member and consultant for io9, has equity and receives income. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. L.B.A. is also a compensated member of the scientific advisory board of Inocras. L.B.A.’s spouse is an employee of Biotheranostics. E.N.B. and L.B.A. declare a US provisional patent application filed with the University of California San Diego with serial number 63/269,033. L.B.A. also declares US provisional applications filed with the University of California San Diego with serial numbers 63/366,392, 63/289,601, 63/483,237, 63/412,835 and 63/492,348. L.B.A. is also an inventor of US patent 10,776,718 for source identification by non-negative matrix factorization. L.B.A. and M.D.-G. further declare a European patent application with application number EP25305077.7. S.-R.Y has received consulting fees from AstraZeneca, Sanofi, Amgen, AbbVie and Sanofi, and speaking fees from AstraZeneca, Medscape, PRIME Education and Medical Learning Institute. The remaining authors declare no competing interests.

References

1. Sun, S., Schiller, J. H. & Gazdar, A. F. Lung cancer in never smokers—a different disease. Nat. Rev. Cancer 7, 778–790 (2007). - PubMed
1. Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74, 229–263 (2024). - PubMed
1. World Health Organization & International Agency for Research on Cancer. Tobacco Smoke and Involuntary Smoking: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 83 (WHO & IARC, 2004).
1. Turner, M. C. et al. Outdoor air pollution and cancer: an overview of the current evidence and public health recommendations. CA Cancer J. Clin. 70, 460–479 (2020).
1. Ciabattini, M., Rizzello, E., Lucaroni, F., Palombi, L. & Boffetta, P. Systematic review and meta-analysis of recent high-quality studies on exposure to particulate matter and risk of lung cancer. Environ. Res. 196, 110440 (2021). - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous