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Mutational signatures associated with tobacco smoking in human cancer
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Abstract
Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clocklike mutational process. Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.
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“TMB measured by comprehensive genomic profiling is comparable to measurements by whole exome sequencing and is typically higher in smoking associated lung cancer due to tobacco carcinogenesis”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [29]
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Cites
Lim, S. S., Vos, T., Flaxman, A. D., Danaei, G., Shibuya, K., Adair-Rohani, H., AlMazroa, M. A., Amann, M., Anderson, H. R., Andrews, K. G., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61766-8 · Cited by 11,805
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660
Self-citationAn integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711
dbSNP: the NCBI database of genetic variation
Sherry, S. T. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.308 · Cited by 7,502
Robust regression using iteratively reweighted least-squares.
Holland, P. W., & Welsch, R. E. (1977) · Communications in Statistics - Theory and Methods · doi:10.1080/03610927708827533 · Cited by 2,115
Mutational Processes Molding the Genomes of 21 Breast Cancers
Nik-Zainal, S., Alexandrov, L. B., Wedge, D. C., Van Loo, P., Greenman, C. D., Raine, K., Jones, D., Hinton, J., Marshall, J., Stebbings, L. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.024 · Cited by 1,909
Self-citationHuber, P. J., & Ronchetti, E. M. (2009) · Wiley series in probability and statistics · doi:10.1002/9780470434697 · Cited by 1,823
Schulze, K., Imbeaud, S., Letouzé, E., Alexandrov, L. B., Calderaro, J., Rebouissou, S., Couchy, G., Meiller, C., Shinde, J., Soysouvanh, F., et al. (2015) · Nature Genetics · doi:10.1038/ng.3252 · Cited by 1,803
Self-citationMapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing
Imielinski, M., Berger, A. H., Hammerman, P. S., Hernandez, B., Pugh, T. J., Hodis, E., Cho, J., Suh, J., Capelletti, M., Sivachenko, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.08.029 · Cited by 1,789
Preferential Formation of Benzo[ a ]pyrene Adducts at Lung Cancer Mutational Hotspots in P53
Denissenko, M. F., Pao, A., Tang, M.-S., & Pfeifer, G. P. (1996) · Science · doi:10.1126/science.274.5286.430 · Cited by 1,650
Flagged first, then by citations
Research works printed but not linked: 2
- D. H. Phillips in The Cancer Handbook M. R. Allison Ed. (Macmillan 2002) pp. 293–306.
- V. Barnett T. Lewis Outliers in Statistical Data (Wiley Series in Probability and Mathematical Statistics: Applied Probability and Statistics Wiley ed. 3 1994).
Cited by
Sorted by citations
Items 401–500 of 1,000
Tafe, L. J. (2019) · Advances in Anatomic Pathology · doi:10.1097/pap.0000000000000244 · Cited by 19
Ono, A., Terada, Y., Kawata, T., Serizawa, M., Isaka, M., Kawabata, T., Imai, T., Mori, K. P., Muramatsu, K., Hayashi, I., et al. (2020) · Cancer Medicine · doi:10.1002/cam4.3107 · Cited by 19
“2 (1-38) ng/mL, median exonic mutation burden (range) 2.”
BackgroundAhn, S., Han, K., Park, Y., Bae, J. M., Kim, S. U., Jeun, S., & Yang, S.-H. (2020) · Cancers · doi:10.3390/cancers12051343 · Cited by 19
“A recent biological study including more than 2000 human tissues samples from various cancers showed multiple distinct mutational signatures induced by smoking, both in tissues directly exposed to smoking and tissues indirectly exposed to smoking [10].”
BackgroundImpact of smoking amount on clinicopathological features and survival in non-small cell lung cancer
Ban, W. H., Yeo, C. D., Han, S., Kang, H. S., Park, C. K., Kim, J. S., Kim, J. W., Kim, S. J., Lee, S. H., & Kim, S. K. (2020) · BMC Cancer · doi:10.1186/s12885-020-07358-3 · Cited by 19
Downregulation of 5‐hydroxymethylcytosine is an early event in pancreatic tumorigenesis
Fujikura, K., Alruwaii, Z. I., Haffner, M. C., Trujillo, M. A. M., Roberts, N. J., Hong, S., Macgregor‐Das, A. M., Goggins, M., Roy, S., Meeker, A. K., et al. (2021) · The Journal of Pathology · doi:10.1002/path.5682 · Cited by 19
“Some of these risk factors, such as tobacco and alcohol exposure, are relatively well understood and have been shown to lead to the accumulation of DNA damage, whereas other factors are still largely unexplored [54,55].”
BackgroundRebello, R. J., Posner, A., Dong, R., Prall, O. W. J., Sivakumaran, T., Mitchell, C. B., Flynn, A., Caneborg, A., Mitchell, C., Kanwal, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59661-x · Cited by 19
Challenges and Perspectives for Immunotherapy in Adenocarcinoma of the Pancreas
Kieler, M., Unseld, M., Bianconi, D., & Prager, G. W. (2018) · Pancreas · doi:10.1097/mpa.0000000000000970 · Cited by 18
Kim, E. Y., Kim, A., Lee, G., Lee, H., & Chang, Y. S. (2018) · BMC Cancer · doi:10.1186/s12885-018-5116-9 · Cited by 18
IL-17-Mediated Inflammation Promotes Cigarette Smoke-Induced Genomic Instability
Cao, C., Tian, B., Geng, X., Zhou, H., Xu, Z., Lai, T., Wu, Y., Bao, Z., Chen, Z., Li, W., et al. (2021) · Cells · doi:10.3390/cells10051173 · Cited by 18
Khanolkar, R. C., Zhang, C., Al-Fatyan, F., Lawson, L., Depasquale, I., Meredith, F. M., Muller, F., Nicolson, M. C., Dahal, L. N., Eid, R. A., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.763877 · Cited by 18
“org 2 important for the generation of effective responses (19, 20).”
BackgroundLiu, Y., Zou, Y.-X., Mu, Z., Wang, J., Tian, S., & Li, Y. (2022) · Current Pharmaceutical Biotechnology · doi:10.2174/1389201023666220307110554 · Cited by 18
Shimoda, Y., Shibaki, R., Yoshida, T., Murakami, S., Shirasawa, M., Torasawa, M., Matsumoto, Y., Masuda, K., Shinno, Y., Okuma, Y., et al. (2022) · Clinical Lung Cancer · doi:10.1016/j.cllc.2022.04.001 · Cited by 18
Morishita, Y., Hasegawa, S., Koie, S., Ueda, S., Miyabe, S., Watanabe, S., Goto, M., Miyachi, H., Nomoto, S., & Nagao, T. (2022) · Tobacco Induced Diseases · doi:10.18332/tid/152510 · Cited by 18
Jiang, Y., Mingard, C., Huber, S. M., Takhaveev, V., McKeague, M., Kizaki, S., Schneider, M., Ziegler, N., Hürlimann, V., Hoeng, J., et al. (2023) · ACS Central Science · doi:10.1021/acscentsci.2c01100 · Cited by 19
Wang, P., Sun, S. B., Lam, S. C., & Lockwood, W. W. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04430-x · Cited by 18
“Single base substitution 4 (SBS4) is a COSMIC mutational signature that is commonly observed in lung cancer tumors of currently tobacco smoking patients, characterized by C> A substitutions resulting from tobacco mutagen exposure [42].”
BackgroundDNA aneuploidy relationship with patient age and tobacco smoke in OPMDs/OSCCs
Castagnola, P., GANDOLFO, S., Malacarne, D., Aiello, C., Marino, R., Zoppoli, G. M., Ballestrero, A., Giaretti, W., & Pentenero, M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0184425 · Cited by 18
Ward, F. J., Dahal, L. N., & Eid, R. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02182 · Cited by 18
“These early experiments in CI therapy highlighted the importance of the mechanisms and environmental cues that drive the release and display of tumor associated and tumor specific neoantigens (62).”
BackgroundModeling clinical and molecular covariates of mutational process activity in cancer
Robinson, W., Sharan, R., & Leiserson, M. D. M. (2019) · Bioinformatics · doi:10.1093/bioinformatics/btz340 · Cited by 18
Clinical and Molecular Correlates of Tumor Mutation Burden in Non-Small Cell Lung Cancer
Sharpnack, M. F., Cho, J. H., Johnson, T. S., Otterson, G. A., Shields, P. G., Huang, K., Carbone, D. P., & He, K. (2020) · Lung Cancer · doi:10.1016/j.lungcan.2020.05.021 · Cited by 18
Carcinogenesis and lung cancer: 70 years of progress and more to come
Samet, J. M. (2020) · Carcinogenesis · doi:10.1093/carcin/bgaa094 · Cited by 18
“passive smoking, radon and air pollution and distinctions described between cancers in smokers and never smokers at the molecular level (16).”
BackgroundInfluentialTumor Mutational Burden Is Polygenic and Genetically Associated with Complex Traits and Diseases
Sun, X., Xue, A., Qi, T., Chen, D., Shi, D., Wu, Y., Zheng, Z., Zeng, J., & Yang, J. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3459 · Cited by 16
“Mutational signatures associated with tobacco smoking were detected and well-characterized in human tumors from large-scale sequencing studies (53).”
BackgroundPrada, D., Belsky, D. W., & Baccarelli, A. (2021) · La Medicina del Lavoro · doi:10.23749/mdl.v112i1.10826 · Cited by 17
“Other studies have suggested that environmental exposures are major drivers of mutation load in somatic tissues, particularly in the lungs, suggesting that mutations and age acceleration might be associated with external exposures (49, 50).”
BackgroundKo, H., Shie, S., Wang, C., Chiu, C., Wang, C.-L., Yang, T., Chou, S.-C., Liu, C., Kuo, C. S., Lin, Y., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1011092 · Cited by 18
“These carcinogens may induce DNA damage, leading to an increased burden of somatic mutations, thereby enhancing the chance of driver mutation development during tumorigenesis (22).”
BackgroundInfluentialGenotoxicity and hypomethylation of LINE-1 induced by electronic cigarettes
Bernal, C., Camero, C., Maria-Jose, P., Sergio, R., Arboleda, A. C., & Rojas, A. P. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.114900 · Cited by 17
Non-Small Cell Lung Cancer Epigenomes Exhibit Altered DNA Methylation in Smokers and Never-Smokers
Karlow, J. A., Pehrsson, E. C., Xing, X., Watson, M. A., Devarakonda, S. H. K., Govindan, R., & Wang, T. (2023) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2023.03.006 · Cited by 18
“This signature is clonal, suggesting that mutations occur before transformation, and correlates with pack years smoked [7].”
Baker, S. C., Arlt, V. M., Indra, R., Joel, M., Stiborová, M., Ian Eardley, C., Ahmad, N., Otto, W., Burger, M., Rubenwolf, P. C., et al. (2018) · Molecular Carcinogenesis · doi:10.1002/mc.22784 · Cited by 17
“Despite strong evidence for the association of smoking and occupational BaP exposure with bladder cancer and the support in this study for urothelial activation of PAHs, the smoking-associated mutational signature seen in lung cancer has not been observed in bladder cancer [7,42].”
BackgroundSelf-citationCharacteristics of mutational signatures of unknown etiology
Hu, X., Xu, Z., & De, S. (2020) · NAR Cancer · doi:10.1093/narcan/zcaa026 · Cited by 18
“tobacco signature (60)], while in other cases broader genomic and epigenomic contexts, which include chromatin, replication timing, processivity and other relevant features, may help understand the mechanisms of DNA damage and DNA repair processes (Figure 3).”
BackgroundThe head and neck cancer genome in the era of immunotherapy
Wijetunga, N. A., Yu, Y., Morris, L. G. T., Lee, N. Y., & Riaz, N. (2020) · Oral Oncology · doi:10.1016/j.oraloncology.2020.105040 · Cited by 17
Chemo-immunotherapy as first-line treatment for small-cell lung cancer
Farid, S., & Liu, S. V. (2020) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758835920980365 · Cited by 17
Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis
Hata, A., Nakajima, T., Matsusaka, K., Fukuyo, M., Nakayama, M., Morimoto, J., Ito, Y., Yamamoto, T., Sakairi, Y., Rahmutulla, B., et al. (2021) · International Journal of Cancer · doi:10.1002/ijc.33499 · Cited by 17
“Smoking is strongly associated with Signatures 4 and 5 harboring C>A transitions.(23) Although most IPF patients were smokers (mean Brinkman Index was 55.”
BackgroundSomatic Mutations in Normal Tissues: New Perspectives on Early Carcinogenesis
Herms, A., & Jones, P. H. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061421-012447 · Cited by 18
Rational design of non-resistant targeted cancer therapies
Martínez-Jiménez, F., Overington, J. P., Al‐Lazikani, B., & Martı́-Renom, M. A. (2017) · Scientific Reports · doi:10.1038/srep46632 · Cited by 17
Identification of a potential tumor suppressor gene, UBL3, in non-small cell lung cancer
Zhao, X., Zhou, Y., Hu, Q., Gao, S., Liu, J., Yu, H., Zhang, Y., Wang, G., Huang, Y., & Zhou, G. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2019.0279 · Cited by 17
“Tobacco smoke causes genomic mutations in cancers 36 ; promotes cell proliferation; inhibits programmed cell death; facilitates angiogenesis, invasion and metastasis; and enhances tumor-promoting inflammation 37,38 .”
Ramos, R., Moura, C. S., Costa, M. F., Lamas, N. J., Castro, L. P. E., Correia, R., Garcez, D., Pereira, J. M., Sousa, C., & Vale, N. (2025) · Pathobiology · doi:10.1159/000544892 · Cited by 16
“SCLC occurs more frequently in smokers, arising from neuroendocrine cells in the airways [14, 30].”
Radon Exposure and Cancer Risk: Assessing Genetic and Protein Markers in Affected Populations
Kashkinbayev, Y., Kazhiyakhmetova, B., Altaeva, N., Bakhtin, M., Tarlykov, P., Saifulina, E., Aumalikova, M., Ibrayeva, D., & Bolatov, A. (2025) · Biology · doi:10.3390/biology14050506 · Cited by 20
“This mutational signature provides a molecular fingerprint that can help distinguish radon-induced cancers from those caused by other etiological factors [61].”
Perduca, V., Omichessan, H., Baglietto, L., & Severi, G. (2017) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000418 · Cited by 15
Benzo[a]pyrene promotes progression in tongue squamous cell carcinoma
Huang, L., Xiao, X., Yao, Y., Yu, J., Chen, Q., Liang, P., & Zhang, Y. (2020) · Oral Diseases · doi:10.1111/odi.13489 · Cited by 17
Risk Factors Associated with Pancreatic Cancer in the UK Biobank Cohort
Ke, T., Lophatananon, A., & Muir, K. R. (2022) · Cancers · doi:10.3390/cancers14204991 · Cited by 16
“In addition, tobacco cigarette smoking was reported [32] to increase the mutational burden for numerous mutational traits, which may be associated with carcinogenesis.”
BackgroundRisk Factors for Cancer: Genetic and Environment
Rahman, M. S., Suresh, S., & Waly, M. I. (2018) · Springer eBooks · doi:10.1007/978-3-319-75693-6_1 · Cited by 19
Autochthonous murine models for the study of smoker and never-smoker associated lung cancers
Akbay, E. A., & Kim, J. (2018) · Translational Lung Cancer Research · doi:10.21037/tlcr.2018.06.04 · Cited by 16
Mismatch repair status and high expression of PD-L1 in nasopharyngeal carcinoma
Zhao, L., Liao, X., Hong, G., Zhuang, Y., Fu, K., Chen, P., Wang, Y., Chen, H., & Lin, Q. (2019) · Cancer Management and Research · doi:10.2147/cmar.s193878 · Cited by 16
Zhang, N., Wu, J., Yu, J., Zhu, H., Yang, M., & Li, R. (2019) · Clinical Lung Cancer · doi:10.1016/j.cllc.2019.10.016 · Cited by 16
Kim, H., Lee, J. S., Lee, J., Chun, H., Ju, Y. S., & Hong, D. (2019) · Genome Medicine · doi:10.1186/s13073-019-0695-x · Cited by 14
“For example, one of the signatures, termed SBS7, features preferential C>T mutations [25], whereas SBS4, a mutational spectrum of tobacco smoke exposure, is characterized by C>A mutations with a strong transcriptional strand bias [26].”
BackgroundSelf-citationTelomere Length in Renal Cell Carcinoma: The Jekyll and Hyde Biomarker of Ageing of the Kidney
Morais, M., Dias, F., Teixeira, A. L., & Medeiros, R. (2020) · Cancer Management and Research · doi:10.2147/cmar.s211225 · Cited by 16
Dutta, M., Nakagawa, H., Kato, H., Maejima, K., Sasagawa, S., Nakano, K., Sasaki-Oku, A., Fujimoto, A., Mateos, R. N., Patil, A., et al. (2020) · PeerJ · doi:10.7717/peerj.9294 · Cited by 16
“Tobacco smoking has been linked to many type of cancers such as lung cancer, liver cancer, esophageal cancer and gastric cancer (Alexandrov et al., 2016).”
BackgroundInfluentialSelf-citationImpact of Host, Lifestyle and Environmental Factors in the Pathogenesis of MPN
Ramanathan, G., Hoover, B., & Fleischman, A. G. (2020) · Cancers · doi:10.3390/cancers12082038 · Cited by 20
Gašperov, N. M., Sabol, I., Božinović, K., Dediol, E., Mravak‐Stipetić, M., Licastro, D., Monego, S. D., & Grce, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186853 · Cited by 16
“The most important risk factors identified so far for HNSCC are excessive tobacco [3,4] and alcohol consumption [5–7], together with high-risk types of human papillomavirus (HPV) [8–10].”
BackgroundAffinito, O., Orlandella, F. M., Luciano, N., Salvatore, M., Salvatore, G., & Franzese, M. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02680-1 · Cited by 16
“Some of these mutational processes are active throughout the lifetime of the cancer cell while other ones are active in a temporal-specific manner [42, 51].”
BackgroundSasagawa, S., Kato, H., Nagaoka, K., Sun, C., Imano, M., Sato, T., Johnson, T. A., Fujita, M., Maejima, K., Okawa, Y., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100705 · Cited by 16
Self-citationIdentification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer
Zhang, Y., Zhao, X., Zhou, Y., Wang, M., & Zhou, G. (2019) · Frontiers of Medicine · doi:10.1007/s11684-019-0708-6 · Cited by 16
Analysis of mutational signatures in C. elegans: Implications for cancer genome analysis
Meier, B., Volkova, N. V., Gerstung, M., & Gartner, A. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102957 · Cited by 17
Uncovering the role of LINE-1 in the evolution of lung adenocarcinoma
Zhang, T., Wei, Z., Wirth, C., Díaz‐Gay, M., Yin, J., Cecati, M., Marchegiani, F., Hoang, P. H., Leduc, C., Baine, M. K., et al. (2025) · Nature · doi:10.1038/s41586-025-09825-y · Cited by 24
Self-citationSpenlé, C., Loustau, T., Burckel, H., Riegel, G., Fayçal, C. A., Li, C., Yilmaz, A., Petti, L., Steinbach, F., Ahowesso, C., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.636108 · Cited by 15
“somatic substitutions located in the translated or untranslated genome regions in patients with smoking-associated HNSCC (top (32), in 4NQO-derived lesions”
BackgroundMethodA mixture model for signature discovery from sparse mutation data
Sason, I., Chen, Y., Leiserson, M. D. M., & Sharan, R. (2021) · Genome Medicine · doi:10.1186/s13073-021-00988-7 · Cited by 15
“Some such mutation signatures have been linked to exposure to specific carcinogens, such as tobacco smoke [6] and ultraviolet radiation [3].”
BackgroundPark, S. L., Marchand, L. L., Cheng, G., Balbo, S., Chen, M., Carmella, S. G., Thomson, N. M., Lee, Y., Patel, Y. M., Stram, D. O., et al. (2022) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.2c00171 · Cited by 15
A lung-specific mutational signature enables inference of viral and bacterial respiratory niche
Ruis, C., Peacock, T. P., Polo, L. M., Masone, D., Álvarez, M. S., Hinrichs, A. S., Turakhia, Y., Ye, C., McBroome, J., Corbett-Detig, R. B., et al. (2023) · Microbial Genomics · doi:10.1099/mgen.0.001018 · Cited by 15
“Each of these mutagens predominantly exerts mutagenic effects through damage of guanine nucleotides [30, 31] and therefore both could drive G>T mutations.”
Elkrief, A., Alessi, J. V., Ricciuti, B., Brown, S., Rizvi, H. A., Preeshagul, I. R., Wang, X., Pecci, F., Federico, A. D., Lamberti, G., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-006994 · Cited by 15
Pelosi, G., Melocchi, V., Dama, E., Hofman, P. M., Luca, M. D., Albini, A., Gemelli, M., Ricotta, R., Papotti, M. G., Rosa, S. L., et al. (2024) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2024.104882 · Cited by 15
Yaacov, A., Cohen, G. B., Landau, J., Hope, T., Simon, I., & Rosenberg, S. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101608 · Cited by 18
“40 The possible disadvantage is more false positives and lower PPV.”
Greco, A., Sánchez-Valle, J., Pancaldi, V., Baudot, A., Barillot, E., Caselle, M., Valencia, A., Zinovyev, A. Y., & Cantini, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133114 · Cited by 16
“Up until now, MF has been successfully used in a broad spectrum of applications: unsupervised clustering, especially in the context of cancer subtyping [5,6], molecular pattern discovery [7,8], mutational signatures definition [9,10] and tumor sample immune infiltration quantification [11].”
MethodPaul, D., Mu, H., Tavakoli, A., Dai, Q., Chen, X.-J., Chakraborty, S., He, C., Ansari, A., Broyde, S., & Min, J.-H. (2020) · bioRxiv · doi:10.1093/nar/gkaa909 · Cited by 13
“Recent genome-wide mapping of DNA damage and cancer mutations also showed that inefficient NER is a major contributor to mutation hotspots in sporadic skin and lung cancers (18-23).”
Geng, D., Guo, Q., Huang, S., Zhang, H., Guo, S., & Li, X. (2021) · Clinical & Translational Oncology · doi:10.1007/s12094-021-02701-x · Cited by 15
“Smoking is associated with increased mutation load of multiple distinct mutational signatures in different cancers types including lung adenocarcinoma [36].”
Huang, C.-C., Lai, C., Tsai, C.-H., Wang, J.-Y., & Wong, R. (2021) · BMC Cancer · doi:10.1186/s12885-021-08800-w · Cited by 15
Pham, T. V., Goodman, A. M., Sivakumar, S., Frampton, G. M., & Kurzrock, R. (2021) · Genome Medicine · doi:10.1186/s13073-021-00979-8 · Cited by 15
Multi-Omics Analysis of the Effects of Smoking on Human Tumors
Wang, R., Li, S., Wen, W., & Zhang, J. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.704910 · Cited by 15
“Similarly, previous studies have found that smoking can induce mutations in multiple genes, which in turn can induce patients to become resistant to chemotherapy drugs (Alexandrov et al., 2016; Shang et al., 2020).”
BackgroundGuo, J., Koopmeiners, J. S., Walmsley, S. J., Villalta, P. W., Yao, L., Murugan, P. J., Tejpaul, R., Weight, C., & Turesky, R. J. (2022) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.2c00012 · Cited by 15
Wahle, B. M., Zolkind, P., Ramirez, R. J., Skidmore, Z. L., Anderson, S. R., Mazul, A. L., Hayes, D. N., Sandulache, V. C., Thorstad, W. L., Adkins, D. R., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104216 · Cited by 15
Research Progress of Axl Inhibitors
Sun, Z., Liu, J., Zhang, J., & Qian, Y. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190620155613 · Cited by 15
Alcohol and smoking habits in association with hepatocellular carcinoma risk
Aglago, E. K., Ramos, I., Keski‐Rahkonen, P., Chatziioannou, A. C., Freisling, H., Fedirko, V., Gunter, M. J., Dahm, C. C., Langmann, F., Bondonno, N. P., et al. (2025) · International Journal of Cancer · doi:10.1002/ijc.35401 · Cited by 14
“12,13 16 Smoking and alcohol differentially contribute to mutation load and DNA damage, 17 activation of proto-oncogenes, 18 and mitochondrial impairment 19 and could synergistically interact to increase HCC risk.”
Wang, G., Wang, Z., Bai, S., Tan, Y., Zhong, W., Sun, G., Liu, Y., Pan, B., Huang, C., Wang, D., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02378-6 · Cited by 15
“24 This degree of transversion is also low in head and neck squamous cell carcinoma, 25 suggesting that the proximal airway might be exposed to tobacco smoke for a shorter time than the distal airway is and thus has lower mutation rates.”
Locken-Castilla, A., Pacheco-Pantoja, E. L., Rodríguez-Brito, F., May‐Kim, S., López-Rivas, V., & Ceballos-Cruz, Á. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0745-7 · Cited by 14
Fu, J., Li, Y., Li, C., Tong, Y., Li, M., & Cang, S. (2021) · Translational Cancer Research · doi:10.21037/tcr-21-565 · Cited by 14
“This could be attributed to the long-term exposure to tobacco smoke in patients with LUAD (35).”
BackgroundOdutola, M. K., van Leeuwen, M. T., Turner, J., Bruinsma, F., Seymour, J. F., Prince, H. M., Milliken, S. T., Trotman, J., Verner, E., Tiley, C., et al. (2022) · Cancers · doi:10.3390/cancers14112710 · Cited by 14
“This DNA nucleotide mutation has been observed in tobacco-related cancers but also in other cancers with no established association with tobacco smoking [60].”
BackgroundWang, H., Hu, J., Wu, J., Ji, P., Shang, A., & Li, D. (2022) · Cancers · doi:10.3390/cancers14215394 · Cited by 14
“There is accumulating evidence that the development of lung cancer is driven by an interplay of hereditary and environmental variables [41].”
BackgroundDissection of Cancer Mutational Signatures with Individual Components of Cigarette Smoking
Mingard, C., Battey, J. N. D., Takhaveev, V., Blatter, K., Hürlimann, V., Sierro, N., Ivanov, N. V., & Sturla, S. J. (2023) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.3c00021 · Cited by 15
Translational research in head and neck cancer: Molecular and immunological updates
Kumai, T., Shinomiya, H., Shibata, H., Takahashi, H., Kishikawa, T., Okada, R., Fujieda, S., & Sakashita, M. (2023) · Auris Nasus Larynx · doi:10.1016/j.anl.2023.08.006 · Cited by 14
Mutational spectra are associated with bacterial niche
Ruis, C., Weimann, A., Tonkin‐Hill, G. Q., Pandurangan, A. P., Matuszewska, M., Murray, G. G. R., Lévesque, R. C., Blundell, T. L., Floto, R. A., & Parkhill, J. (2023) · Nature Communications · doi:10.1038/s41467-023-42916-w · Cited by 21
“Reconstructing theset ofmutationsandsignatureswithin cancers has enabled inference of the drivers of tumourigenesis 1,2,7 .”
Chemoproteogenomic stratification of the missense variant cysteinome
Desai, H. S., Andrews, K. H., Bergersen, K. V., Ofori, S., Yu, F., Shikwana, F., Arbing, M. A., Boatner, L. M., Villanueva, M., Ung, N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53520-x · Cited by 24
Henick, B. S., Taylor, A. M., Nakagawa, H., Wong, K., Diehl, J. A., & Rustgi, A. K. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.01.003 · Cited by 17
Self-citationKanellakis, N. I., Giannou, A. D., Pepe, M. A. A., Agalioti, T., Zazara, D. E., Giopanou, I., Psallidas, I., Σπέλλα, Μ., Marazioti, A., Arendt, K. A. M., et al. (2019) · Carcinogenesis · doi:10.1093/carcin/bgz047 · Cited by 12
Effects of Inhaled Tobacco Smoke on the Pulmonary Tumor Microenvironment
Giotopoulou, G. A., & Stathopoulos, G. T. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-35727-6_4 · Cited by 14
Oiwa, H., Aokage, K., Suzuki, A., Sato, K. A., Kuroe, T., Mimaki, S., Tane, K., Miyoshi, T., Samejima, J., Tsuchihara, K., et al. (2021) · Lung Cancer · doi:10.1016/j.lungcan.2021.07.001 · Cited by 14
Keith, N., Jackson, C. E., Glaholt, S., Young, K., Lynch, M., & Shaw, J. R. (2021) · Environmental Health Perspectives · doi:10.1289/ehp8932 · Cited by 14
“The analysis of chemical stressor-induced genome-wide mutation signatures in tumors has been important for linking chemicals to their perturbation of speci fi c polymerases and DNA repair pathways, genome-wide (Alexandrov et al. 2016; Supek and Lehner 2017).”
Kim, J., Ha, H., Park, J., Cho, J., Lim, J. H., & Lee, M. H. (2021) · Journal of Cancer · doi:10.7150/jca.65374 · Cited by 13
“Smoking can influence TMB level via the accumulation of somatic mutations by carcinogens in tobacco, leading to a higher neoantigen load [26].”
BackgroundSaravia, R., Ten-Blanco, M., Pereda-Pérez, I., & Berrendero, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413316 · Cited by 14
How tobacco smoke changes the (epi)genome
Pfeifer, G. P. (2016) · Science · doi:10.1126/science.aal2114 · Cited by 14
Wang, S. J., Asthana, S., van Zante, A., Heaton, C. M., Phuchareon, J., Stein, L. C., Higuchi, S., Kishimoto, T., Chiu, C. Y., Olshen, A. B., et al. (2017) · Oral Oncology · doi:10.1016/j.oraloncology.2017.03.020 · Cited by 14
“A recent report with the TCGA database showed that In/Del frequencies do not differ between smokers and neversmokers [45].”
Lung Cancer, Smoking, and Obesity: It’s Complicated
Samet, J. M. (2018) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djy019 · Cited by 13
Jahreiß, M.-C., Aben, K. K. H., Hoogeman, M. S., Dirkx, M. L. P., de Vries, K. C., Incrocci, L., & Heemsbergen, W. D. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.605119 · Cited by 14
“Based on our results, more scatter dose associated with IMRT combined with active smoking and its associated presence of mutations in organs (30) might have caused additional risks.”
BackgroundEditorial: Is the Incidence of Adenocarcinoma of the Lung Rising in Never Smokers?
Samet, J. M. (2017) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw325 · Cited by 14
“(7) compared a set of 96 mutational signatures in the genomes of adenocarcinomas from smokers and never smokers, finding far higher mutation rates and prominence of specific signatures in the cancers from smokers vs those from never smokers.”
BackgroundWang, J., Linxweiler, M., Yang, W., Chan, T. A.-T., & Morris, L. G. T. (2019) · Oncotarget · doi:10.18632/oncotarget.26982 · Cited by 13
“Tobacco smoke contains many carcinogenic chemicals that disrupt DNA such as polycyclic aromatic hydrocarbons and nitrosamines, which can cause G→T transversions and distinct mutational signatures [6, 7].”
BackgroundWang, H., Liu, J., Zhu, S., Miao, K., Li, Z., Qi, X., Huang, L., Guo, L., Wang, Y., Cai, Y., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.945843 · Cited by 13
“In ADC, Signatures 2 and 13 display a higher number of mutations in smokers as compared to non-smokers (26).”
BackgroundApproaches for the setting of occupational exposure limits (OELs) for carcinogens
Högberg, J., & Järnberg, J. (2023) · Critical Reviews in Toxicology · doi:10.1080/10408444.2023.2218887 · Cited by 18
“…effect of a non-threshold carcinogen is likely amplified by threshold effects such as inflammation and cell death that cause additional, indirect DNA damage or adversely affect DNA repair (Balkwill et al. 2005; Alexandrov et al. 2016; Shi et al. 2017; Benesch et al. 2018; Golemis et al. 2018).”
BackgroundShalata, W., Rabinovich, N. M., Agbarya, A., Yakobson, A., Dudnik, Y., Jama, A. A., Cohen, A. Y., Shalata, S., Hamed, A. A., Ber, T. I., et al. (2024) · Cancers · doi:10.3390/cancers16101825 · Cited by 13
Arenillas, C., Celada, L., Ruiz-Cantador, J., Calsina, B., Datta, D., García‐Galea, E., Fasani, R., Moreno-Cárdenas, A. B., Alba‐Linares, J. J., Miranda, B., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0943 · Cited by 14
Surien, O., Ghazali, A. R., & Masre, S. F. (2019) · Biomedical & Pharmacology Journal · doi:10.13005/bpj/1617 · Cited by 13
Cancer mutational signatures representation by large-scale context embedding
Zhang, Y., Xiao, Y., Yang, M., & Ma, J. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btaa433 · Cited by 13
Năstase, A., Mansuet‐Lupo, A., LASZLO, V., Damotte, D., Dima, S., Canny, E., Alifano, M., Popescu, I., Klepetko, W., & Grigoroiu, M. (2020) · Cancer Genomics & Proteomics · doi:10.21873/cgp.20215 · Cited by 13
APOBEC3B deletion polymorphism and lung cancer risk in the southern Chinese population
Ben, X., Tian, D., Liang, J., Wu, M., Xie, F., Zheng, J., Chen, J., Fei, Q., Guo, X., Weng, X., et al. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-989 · Cited by 12
“Smoking can also cause gene mutations which may lead to a heavy mutation load of lung cancer (6,7).”
Lupo, P. J., Petrick, L. M., Hoang, T. T., Janitz, A. E., Marcotte, E. L., Schraw, J. M., Arora, M., & Scheurer, M. E. (2021) · BioEssays · doi:10.1002/bies.202100030 · Cited by 16
Metadata
- Authors
- Alexandrov, L. B., Ju, Y. S., Haase, K., Van Loo, P., Martincorena, I., Nik-Zainal, S., Totoki, Y., Fujimoto, A., Nakagawa, H., Shibata, T., Campbell, P. J., Vineis, P., Phillips, D. H., & Stratton, M. R.
- Affiliations
- Los Alamos National Laboratory (US)
- Korea Advanced Institute of Science and Technology (KR)
- The Francis Crick Institute (GB)
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
- Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
- National Cancer Center Research Institute (JP)
- Kyoto University (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- University of Cambridge (GB)
- Public Health England (GB)
- King's College London (GB)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Alexandrov, Ludmil B.
- Stratton, Michael R.
- ORCID
- Venue
- Science
- Published
- 2016-11-04
- Volume
- 354
- Issue
- 6312
- Pages
- 618-622
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6141049
- OpenAlex
- W2547187744
- Cited by
- 1,100
- References
- 54
- Citations by year
- 2026: 70 · 2025: 89 · 2024: 103 · 2023: 121 · 2022: 115 · 2021: 148 · 2020: 149 · 2019: 117 · 2018: 95 · 2017: 90 · 2016: 3
- FWCI
- 42.36
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Lirias (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Wellcome Trust Intermediate Fellowship (WT100183MA)
- Wellcome Trust Senior Clinical Research Fellowship (WT088340MA)
- U.S. Department of Energy (DOE) National Nuclear Security Administration (DE-AC52-06NA25396)
- Francis Crick Institute
- UK MRC (FC001202)
- Cancer Research UK (FC001202, C313/A14329)
- Wellcome Trust (98051, FC001202, 101126/Z/13/Z, 101126/B/13/Z)
- National Institute for Health Research (NIHR)
- EXPOSOMICS (308610-FP7)
- Japan Agency for Medical Research and Development (15ck0106094h0002)
- National Cancer Center Research and Development Funds (26-A-5)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- smoking, mutational signatures, somatic mutations, DNA methylation, tobacco-related cancer, APOBEC cytidine deaminases, tobacco carcinogens, mutational burden, cancer risk
- MeSH terms
- APOBEC Deaminases, Carcinogens, DNA Damage, Humans, Mutation, Neoplasms, Risk, Smoking, Tobacco Products, Nicotiana, CpG Islands, DNA Methylation, Exome
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