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

Zobrazit více v PubMed

Sun, S., Schiller, J. H. & Gazdar, A. F. Lung cancer in never smokers—a different disease. Nat. Rev. Cancer 7, 778–790 (2007). PubMed DOI

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 DOI

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).

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). DOI

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 DOI

Senkin, S. et al. Geographic variation of mutagenic exposures in kidney cancer genomes. Nature 629, 910–918 (2024). PubMed DOI PMC

Poon, S. L. et al. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci. Transl. Med. 5, 197ra101 (2013). PubMed DOI

Hoang, M. L. et al. Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci. Transl. Med. 5, 197ra102 (2013). PubMed DOI PMC

Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). PubMed DOI PMC

Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015). PubMed DOI PMC

Proctor, R. N. Tobacco and the global lung cancer epidemic. Nat. Rev. Cancer 1, 82–86 (2001). PubMed DOI

Siegel, D. A., Fedewa, S. A., Henley, S. J., Pollack, L. A. & Jemal, A. Proportion of never smokers among men and women with lung cancer in 7 US states. JAMA Oncol. 7, 302–304 (2021). PubMed DOI

Lui, N. S. et al. Sub-solid lung adenocarcinoma in Asian versus Caucasian patients: different biology but similar outcomes. J. Thorac. Dis. 12, 2161–2171 (2020). PubMed DOI PMC

Gaughan, E. M., Cryer, S. K., Yeap, B. Y., Jackman, D. M. & Costa, D. B. Family history of lung cancer in never smokers with non-small-cell lung cancer and its association with tumors harboring EGFR mutations. Lung Cancer 79, 193–197 (2013). PubMed DOI

Toh, C. K. et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J. Clin. Oncol. 24, 2245–2251 (2006). PubMed DOI

Yano, T. et al. Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer 113, 1012–1018 (2008). PubMed DOI

Brennan, P. et al. High cumulative risk of lung cancer death among smokers and nonsmokers in Central and Eastern Europe. Am. J. Epidemiol. 164, 1233–1241 (2006). PubMed DOI

Wang, P., Sun, S., Lam, S. & Lockwood, W. W. New insights into the biology and development of lung cancer in never smokers—implications for early detection and treatment. J. Transl. Med. 21, 585 (2023). PubMed DOI PMC

Koh, G., Degasperi, A., Zou, X., Momen, S. & Nik-Zainal, S. Mutational signatures: emerging concepts, caveats and clinical applications. Nat. Rev. Cancer 21, 619–637 (2021). PubMed DOI

Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020). PubMed DOI PMC

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020). DOI

Wang, X. et al. Association between smoking history and tumor mutation burden in advanced non-small cell lung cancer. Cancer Res. 81, 2566–2573 (2021). PubMed DOI PMC

Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019). PubMed DOI

Zhang, T. et al. Genomic and evolutionary classification of lung cancer in never smokers. Nat. Genet. 53, 1348–1359 (2021). PubMed DOI PMC

Landi, M. T. et al. Tracing lung cancer risk factors through mutational signatures in never-smokers: the Sherlock-Lung study. Am. J. Epidemiol. 190, 962–976 (2021). PubMed DOI

Auton, A. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015). PubMed DOI

Islam, S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell Genom. 2, 100179 (2022). PubMed DOI PMC

Sondka, Z. et al. COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Res. 52, D1210–D1217 (2024). PubMed DOI

Zou, X. et al. A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage. Nat. Cancer 2, 643–657 (2021). PubMed DOI PMC

Steele, C. D. et al. Signatures of copy number alterations in human cancer. Nature 606, 984–991 (2022). PubMed DOI PMC

Everall, A. et al. Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types from 10,983 cancer patients. Preprint at medRxiv https://doi.org/10.1101/2023.06.07.23290970 (2023).

Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016). PubMed DOI PMC

Degasperi, A. et al. A practical framework and online tool for mutational signature analyses show inter-tissue variation and driver dependencies. Nat. Cancer 1, 249–263 (2020). PubMed DOI PMC

Huang, K. L. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370 (2018). PubMed DOI PMC

Nguyen, L., Martens, J. W. M., Van Hoeck, A. & Cuppen, E. Pan-cancer landscape of homologous recombination deficiency. Nat. Commun. 11, 5584 (2020). PubMed DOI PMC

Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017). PubMed DOI PMC

Zhang, T. et al. Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition. Preprint at bioRxiv https://doi.org/10.1101/2025.03.14.643063 (2025).

Letouze, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017). PubMed DOI PMC

Fujimoto, A. et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat. Genet. 48, 500–509 (2016). PubMed DOI

Swanton, C., McGranahan, N., Starrett, G. J. & Harris, R. S. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov. 5, 704–712 (2015). PubMed DOI PMC

Chen, Y.-J. et al. Proteogenomics of non-smoking lung cancer in East Asia delineates molecular signatures of pathogenesis and progression. Cell 182, 226–244 (2020). PubMed DOI

Zhang, T. et al. APOBEC affects tumor evolution and age at onset of lung cancer in smokers. Nat. Commun. 16, 4711 (2025). PubMed DOI PMC

Morton, L. M. et al. Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident. Science 372, eabg2538 (2021). PubMed DOI PMC

Lawson, A. R. J. et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science 370, 75–82 (2020). PubMed DOI

Degasperi, A. et al. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science 376, abl9283 (2022). DOI

Otlu, B. et al. Topography of mutational signatures in human cancer. Cell Rep. 42, 112930 (2023). PubMed DOI PMC

Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017). PubMed DOI

Zhang, T. et al. Distinct genomic landscape of lung adenocarcinoma from household use of smoky coal. Am. J. Respir. Crit. Care Med. 208, 733–736 (2023). PubMed DOI PMC

Hill, W. et al. Lung adenocarcinoma promotion by air pollutants. Nature 616, 159–167 (2023). PubMed DOI PMC

van Donkelaar, A. et al. Monthly global estimates of fine particulate matter and their uncertainty. Environ. Sci. Technol. 55, 15287–15300 (2021). PubMed DOI

Mochizuki, A. et al. Passive smoking-induced mutagenesis as a promoter of lung carcinogenesis. J. Thorac. Oncol. 19, 984–994 (2024). PubMed DOI

Yu, X. J. et al. Characterization of somatic mutations in air pollution-related lung cancer. EBioMedicine 2, 583–590 (2015). PubMed DOI PMC

Chan, W.-H. et al. Verifying the accuracy of self-reported smoking behavior in female volunteer soldiers. Sci. Rep. 13, 3438 (2023). PubMed DOI PMC

Landi, M. T. et al. Environment And Genetics in Lung cancer Etiology (EAGLE) study: an integrative population-based case–control study of lung cancer. BMC Public Health 8, 203 (2008). PubMed DOI PMC

Bergmann, E. A., Chen, B. J., Arora, K., Vacic, V. & Zody, M. C. Conpair: concordance and contamination estimator for matched tumor–normal pairs. Bioinformatics 32, 3196–3198 (2016). PubMed DOI PMC

Pedersen, B. S. et al. Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches. Genome Med. 12, 62 (2020). PubMed DOI PMC

Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012). PubMed DOI PMC

Boot, A. et al. In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors. Genome Res. 28, 654–665 (2018). PubMed DOI PMC

Dentro, S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239–2254 (2021). PubMed DOI PMC

Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012). PubMed DOI PMC

Lee, J. K. et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J. Clin. Oncol. 35, 3065–3074 (2017). PubMed DOI

The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). DOI PMC

Carrot-Zhang, J. et al. Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway. Cell Rep. 34, 108707 (2021). PubMed DOI PMC

Pedersen, B. S. & Quinlan, A. R. Mosdepth: quick coverage calculation for genomes and exomes. Bioinformatics 34, 867–868 (2018). PubMed DOI

Sadedin, S. P. & Oshlack, A. Bazam: a rapid method for read extraction and realignment of high-throughput sequencing data. Genome Biol. 20, 78 (2019). PubMed DOI PMC

Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013). PubMed DOI PMC

Kim, S. et al. Strelka2: fast and accurate calling of germline and somatic variants. Nat. Methods 15, 591–594 (2018). PubMed DOI

Freed, D., Pan, R. & Aldana, R. TNscope: accurate detection of somatic mutations with haplotype-based variant candidate detection and machine learning filtering. Preprint at bioRxiv https://doi.org/10.1101/250647 (2018).

Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). PubMed DOI PMC

Ramos, A. H. et al. Oncotator: cancer variant annotation tool. Hum. Mutat. 36, E2423–E2429 (2015). PubMed DOI

Hasan, M. S., Wu, X., Watson, L. T. & Zhang, L. UPS-indel: a universal positioning system for indels. Sci. Rep. 7, 14106 (2017). PubMed DOI PMC

Mayakonda, A., Lin, D. C., Assenov, Y., Plass, C. & Koeffler, H. P. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 28, 1747–1756 (2018). PubMed DOI PMC

Jun, G. et al. Detecting and estimating contamination of human DNA samples in sequencing and array-based genotype data. Am. J. Hum. Genet. 91, 839–848 (2012). PubMed DOI PMC

Martinez-Jimenez, F. et al. A compendium of mutational cancer driver genes. Nat. Rev. Cancer 20, 555–572 (2020). PubMed DOI

Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171, 1029–1041 (2017). PubMed DOI PMC

Sondka, Z. et al. The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers. Nat. Rev. Cancer 18, 696–705 (2018). PubMed DOI PMC

Muiños, F., Martinez-Jimenez, F., Pich, O., Gonzalez-Perez, A. & Lopez-Bigas, N. In silico saturation mutagenesis of cancer genes. Nature 596, 428–432 (2021). PubMed DOI

Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. 2017, 1–16 (2017). DOI

Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385 (2018). PubMed DOI PMC

Cheng, J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492 (2023). PubMed DOI

Yuan, K., Macintyre, G., Liu, W., PCAWG-11 working group & Markowetz, F. Ccube: a fast and robust method for estimating cancer cell fractions. Preprint at bioRxiv https://doi.org/10.1101/484402 (2018).

Mermel, C. H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011). PubMed DOI PMC

Yang, L. et al. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153, 919–929 (2013). PubMed DOI PMC

Chen, X. et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016). PubMed DOI

Yang, Y. & Yang, L. Somatic structural variation signatures in pediatric brain tumors. Cell Rep. 42, 113276 (2023). PubMed DOI PMC

Zhu, H. et al. Candidate cancer driver mutations in distal regulatory elements and long-range chromatin interaction networks. Mol. Cell 77, 1307–1321 (2020). PubMed DOI

Ding, Z. et al. Estimating telomere length from whole genome sequence data. Nucleic Acids Res. 42, e75 (2014). PubMed DOI PMC

Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Campbell, P. J. & Stratton, M. R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013). PubMed DOI PMC

Bergstrom, E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genomics 20, 685 (2019). PubMed DOI PMC

Díaz-Gay, M. et al. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment. Bioinformatics 39, btad756 (2023). PubMed DOI PMC

Otlu, B. & Alexandrov, L. B. Evaluating topography of mutational signatures with SigProfilerTopography. Genome Biol. 26, 134 (2025). PubMed DOI PMC

Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate—a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995). DOI