Sun, S., Schiller, J. H. & Gazdar, A. F. Lung cancer in never smokers—a different disease. Nat. Rev. Cancer 7, 778–790 (2007).
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).
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).
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).
Senkin, S. et al. Geographic variation of mutagenic exposures in kidney cancer genomes. Nature 629, 910–918 (2024).
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).
Hoang, M. L. et al. Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci. Transl. Med. 5, 197ra102 (2013).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015).
Proctor, R. N. Tobacco and the global lung cancer epidemic. Nat. Rev. Cancer 1, 82–86 (2001).
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).
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).
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).
Toh, C. K. et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J. Clin. Oncol. 24, 2245–2251 (2006).
Yano, T. et al. Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer 113, 1012–1018 (2008).
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).
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).
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).
Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).
The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).
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).
Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019).
Zhang, T. et al. Genomic and evolutionary classification of lung cancer in never smokers. Nat. Genet. 53, 1348–1359 (2021).
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).
Auton, A. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
Islam, S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell Genom. 2, 100179 (2022).
Sondka, Z. et al. COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Res. 52, D1210–D1217 (2024).
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).
Steele, C. D. et al. Signatures of copy number alterations in human cancer. Nature 606, 984–991 (2022).
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).
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).
Huang, K. L. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370 (2018).
Nguyen, L., Martens, J. W. M., Van Hoeck, A. & Cuppen, E. Pan-cancer landscape of homologous recombination deficiency. Nat. Commun. 11, 5584 (2020).
Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017).
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).
Fujimoto, A. et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat. Genet. 48, 500–509 (2016).
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).
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).
Zhang, T. et al. APOBEC affects tumor evolution and age at onset of lung cancer in smokers. Nat. Commun. 16, 4711 (2025).
Morton, L. M. et al. Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident. Science 372, eabg2538 (2021).
Lawson, A. R. J. et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science 370, 75–82 (2020).
Degasperi, A. et al. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science 376, abl9283 (2022).
Otlu, B. et al. Topography of mutational signatures in human cancer. Cell Rep. 42, 112930 (2023).
Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).
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).
Hill, W. et al. Lung adenocarcinoma promotion by air pollutants. Nature 616, 159–167 (2023).
van Donkelaar, A. et al. Monthly global estimates of fine particulate matter and their uncertainty. Environ. Sci. Technol. 55, 15287–15300 (2021).
Mochizuki, A. et al. Passive smoking-induced mutagenesis as a promoter of lung carcinogenesis. J. Thorac. Oncol. 19, 984–994 (2024).
Yu, X. J. et al. Characterization of somatic mutations in air pollution-related lung cancer. EBioMedicine 2, 583–590 (2015).
Chan, W.-H. et al. Verifying the accuracy of self-reported smoking behavior in female volunteer soldiers. Sci. Rep. 13, 3438 (2023).
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).
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).
Pedersen, B. S. et al. Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches. Genome Med. 12, 62 (2020).
Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).
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).
Dentro, S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239–2254 (2021).
Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).
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).
The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Carrot-Zhang, J. et al. Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway. Cell Rep. 34, 108707 (2021).
Pedersen, B. S. & Quinlan, A. R. Mosdepth: quick coverage calculation for genomes and exomes. Bioinformatics 34, 867–868 (2018).
Sadedin, S. P. & Oshlack, A. Bazam: a rapid method for read extraction and realignment of high-throughput sequencing data. Genome Biol. 20, 78 (2019).
Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).
Kim, S. et al. Strelka2: fast and accurate calling of germline and somatic variants. Nat. Methods 15, 591–594 (2018).
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).
Ramos, A. H. et al. Oncotator: cancer variant annotation tool. Hum. Mutat. 36, E2423–E2429 (2015).
Hasan, M. S., Wu, X., Watson, L. T. & Zhang, L. UPS-indel: a universal positioning system for indels. Sci. Rep. 7, 14106 (2017).
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).
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).
Martinez-Jimenez, F. et al. A compendium of mutational cancer driver genes. Nat. Rev. Cancer 20, 555–572 (2020).
Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171, 1029–1041 (2017).
Sondka, Z. et al. The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers. Nat. Rev. Cancer 18, 696–705 (2018).
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).
Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. 2017, 1–16 (2017).
Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385 (2018).
Cheng, J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492 (2023).
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).
Yang, L. et al. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153, 919–929 (2013).
Chen, X. et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016).
Yang, Y. & Yang, L. Somatic structural variation signatures in pediatric brain tumors. Cell Rep. 42, 113276 (2023).
Zhu, H. et al. Candidate cancer driver mutations in distal regulatory elements and long-range chromatin interaction networks. Mol. Cell 77, 1307–1321 (2020).
Ding, Z. et al. Estimating telomere length from whole genome sequence data. Nucleic Acids Res. 42, e75 (2014).
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).
Bergstrom, E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genomics 20, 685 (2019).
Díaz-Gay, M. et al. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment. Bioinformatics 39, btad756 (2023).
Otlu, B. & Alexandrov, L. B. Evaluating topography of mutational signatures with SigProfilerTopography. Genome Biol. 26, 134 (2025).
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).