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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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BackgroundUnraveling the genomic landscape of colorectal cancer through mutational signatures
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Self-citationA role for club cells in smoking-associated lung adenocarcinoma
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Pfeifer, G. P., & Jin, S. (2024) · Nature Reviews Genetics · doi:10.1038/s41576-024-00748-4 · Cited by 26
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“Tobacco use is known to increase point mutations [30] and is an established risk factor for EA [58, 59].”
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“These mutagenic processes include disruptions to the DNA damage repair pathway [94], environmental insults such as smoking [95] and UV radiation, and chemotherapy [96].”
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BackgroundWithin-host bacterial evolution and the emergence of pathogenicity
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“Furthermore, our sample confirmed several trends that have been demonstrated by multiple larger studies and which are embraced in the literature, including that higher TMB is associated with smoking [18], and that targetable mutations are found more commonly in non-smokers [19].”
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“It has also become apparent that certain signatures show a dose-response relationship with risk factors, for example COSMIC signature SBS4 with tobacco smoking[5].”
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“It is suggested that the cellular machinery underlying SBS2 and SBS13 is activated by tobacco smoke via direct or indirect pathways [27].”
BackgroundAntibody-Drug Conjugate Targeting c-Kit for the Treatment of Small Cell Lung Cancer
Kim, K., Kim, J.-O., Park, J.-Y., Seo, M., & Park, S. G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042264 · Cited by 22
“In addition, most SCLC patients are current or former heavy smokers, which is associated with a high tumor mutational burden, with C:G > A:T transversions being the most common type of base substitutions [13,14] The c-Kit proto-oncogene encodes a transmembrane tyrosine kinase growth factor receptor that belongs to the…”
BackgroundAffolter, A., Kern, J., Bieback, K., Scherl, C., Rotter, N., & Lammert, A. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5378 · Cited by 22
“(mutant‐allele tumor heterogeneity) score (48) which is not in line with former observations that carcinogens in tobacco smoke are expected to cause permanent DNA damage reflected in TMB (54).”
BackgroundInfluentialBalmain, A. (2022) · European Journal of Epidemiology · doi:10.1007/s10654-022-00933-x · Cited by 22
“…two mechanistic advances, i.e. the demonstration that cigarette smoke has both mutagenic and promoting activities, only the former was followed up systematically, culminating in identification of precise mutational signatures showing exactly how tobacco carcinogens cause mutations in DNA [32].”
BackgroundUgai, T., Matsuo, K., Oze, I., Ito, H. M., Wakai, K., Wada, K., Nagata, C., Nakayama, T., Liu, R., Kitamura, Y. T., et al. (2017) · Hematological Oncology · doi:10.1002/hon.2457 · Cited by 22
“Genetic mutations associated with leukaemogenesis can occur following exposure to toxic chemical components in cigarettes.(24) One of the most likely mechanisms of the leukaemogenic effect of smoking leads is through benzene.”
BackgroundLiu, Q., Han, H., Wang, M., Yao, Y., Li, W., Jiang, K., Ma, Y., Fan, R., Chen, J., Su, K., et al. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0130-x · Cited by 25
Shiba‐Ishii, A. (2021) · Pathology International · doi:10.1111/pin.13147 · Cited by 23
“Of note, Tg‐SPC‐SFN tumors showed a distinct signature that is similar to the COSMIC signatures 4 and 24,(33) which show a high frequency of C > A.(57) Consistent with our results, TCGA also indicated that signatures 4 and 24 were frequently observed in human lung adenocarcinoma and showed a high frequency of C > A an…”
ResultKoutros, S., Rao, N., Moore, L. E., Nickerson, M. L., Lee, D., Zhu, B., Pardo, L. A., Baris, D., Schwenn, M. R., Johnson, A. T., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-4419 · Cited by 21
“Although this link has not been reported before in bladder cancer, pack-years of smoking has been linked to elevated APOBEC-Signature 13 mutational burden in smokers with lung adenocarcinoma (25, 30).”
BackgroundInfluentialWillis, A. J., Indra, R., Wohak, L. E., Sözeri, O., Feser, K., Mrízová, I., Phillips, D. H., Stiborová, M., & Arlt, V. M. (2018) · Toxicology · doi:10.1016/j.tox.2018.02.006 · Cited by 21
Self-citationStem cell replication, somatic mutations and role of randomness in the development of cancer
Perduca, V., Alexandrov, L. B., Kelly‐Irving, M., Delpierre, C., Omichessan, H., Little, M. P., Vineis, P., & Severi, G. (2019) · European Journal of Epidemiology · doi:10.1007/s10654-018-0477-6 · Cited by 21
Self-citationThe Impending Epidemic of Cardiovascular Diseases in Patients With Cancer in Japan
Okura, Y., Ozaki, K., Tanaka, H., Takenouchi, T., Sato, N., & Minamino, T. (2019) · Circulation Journal · doi:10.1253/circj.cj-19-0426 · Cited by 22
Zhang, H., Song, Y., Du, Z., Li, X., Zhang, J., Chen, S., Chen, F., Li, T., & Zhan, Q. (2020) · The Journal of Pathology · doi:10.1002/path.5467 · Cited by 21
“Moreover, lifestyle, diet habits, and ethnicity can also affect the genomic landscape of TSCC, and TSCC etiology varies across geographical regions [9,12].”
BackgroundStabile, L. P., Kumar, V., Gaither‐Davis, A., Huang, E. H. ‐., Vendetti, F. P., Devadassan, P., Đačić, S., Bao, R., Steinman, R. A., Burns, T. F., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.145307 · Cited by 23
“While gene expression signatures in NNK-induced lung tumors are highly comparable to those found in human LUAD (21), our knowledge of the murine mutational landscape, such as the smoking-associated mutational patterns characterized in human LUAD (22), is limited.”
BackgroundMiyauchi, E., Matsuda, T., Kiyotani, K., Low, S., Hsu, Y., Tsukita, Y., Ichinose, M., Sakurada, A., Okada, Y., Saito, R., et al. (2018) · Cancer Science · doi:10.1111/cas.13919 · Cited by 20
Mechanism of error-free replication across benzo[a]pyrene stereoisomers by Rev1 DNA polymerase
Rechkoblit, O., Kolbanovskiy, A., Landes, H., Geacintov, N. E., & Aggarwal, A. K. (2017) · Nature Communications · doi:10.1038/s41467-017-01013-5 · Cited by 20
Rajagopalan, P., Patel, K., Jain, A., Nanjappa, V., Datta, K. K., Subbannayya, T., Mangalaparthi, K. K., Kumari, A., Manoharan, M., Coral, K., et al. (2018) · Cancer Biology & Therapy · doi:10.1080/15384047.2018.1470724 · Cited by 20
“A transversions in smokers.(55) Whole exome sequencing (WES) revealed an increased rate of C>A transversions in oral cells upon chronic smoke exposure.”
BackgroundEpidemiological Correlations Between Head and Neck Cancer and Hepatitis B Core Antibody Positivity
Komori, M., Kimura, T., Kariya, S., Onoda, T., Takeda, S., Mizukawa, N., Iida, S., Kimata, Y., & Nishizaki, K. (2020) · Anticancer Research · doi:10.21873/anticanres.14209 · Cited by 20
Supervised mutational signatures for obesity and other tissue-specific etiological factors in cancer
Afsari, B., Kuo, A., Zhang, Y., Li, L., Lahouel, K., Danilova, L., Favorov, A. V., Rosenquist, T. A., Grollman, A. P., Kinzler, K. W., et al. (2021) · eLife · doi:10.7554/elife.61082 · Cited by 20
“…studies of signatures, it has been assumed that a specific mutational process produces the same signature in all tissue types (Alexandrov et al., 2015; Alexandrov et al., 2016; Alexandrov et al., 2013b; Alexandrov et al., 2013a; see Blokzijl et al., 2016; Hoang et al., 2013 for exceptions).”
BackgroundMethodInfluentialLin, L.-H., Chou, C., Cheng, H.-W., Chang, K., & Liu, C. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.741626 · Cited by 21
“The accumulation of somatic mutations within a cancer genome has revealed that certain oncogenic patterns are associated with the exposure to mutagens and with defects in DNA repair (15, 16).”
BackgroundA quantitative method for assessing smoke associated molecular damage in lung cancers
Song, K., Bi, J.-H., Qiu, Z.-W., Felizardo, R., Girard, L., Minna, J. D., & Gazdar, A. F. (2018) · Translational Lung Cancer Research · doi:10.21037/tlcr.2018.07.01 · Cited by 20
“These findings are consistent with the proposition that tobacco exposure results in cancer risk by increasing the somatic mutation load, both in number and type (1).”
BackgroundResultInfluentialThe value of immunotherapy in head and neck cancer
Manca, P., Raez, L., Salzberg, M., Sánchez, J., Hunis, B., & Rolfo, C. (2019) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2019.1556637 · Cited by 16
“widely accepted that smoking-related tumors harbor an increased number of mutations [40] and that mutational load”
BackgroundSaddawi‐Konefka, R., Simon, A. B., Sumner, W., Sharabi, A. B., Mell, L. K., & Cohen, E. E. W. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.738626 · Cited by 22
“However, based upon several studies of common mutational signatures amongst human cancers (48–50), early GEMMs have come under scrutiny for featuring genetic alterations rarely seen in HNSCC and lacking the signature mutanomes now associated with both human papillomavirus (HPV)-positive and HPV-negative HNSCC (49, 50).”
BackgroundSzyfter, K., Napierała, M., Florek, E., Braakhuis, B. J. M., Takes, R. P., Rodrigo, J. P., Rinaldo, A., Silver, C. E., & Ferlito, A. (2018) · International Journal of Cancer · doi:10.1002/ijc.31846 · Cited by 20
“Some differences between profiles of aromatic DNA adducts and C>T mutation were explained by ongoing selection process.70 Concerning TP53 mutations in head and neck cancer C>T transversions were found as the most frequent.71 The publication of Alexandrov et al.72 provides signatures of 17 classes of cancer where tobac…”
BackgroundThe genomic landscape of lung cancer in never-smokers from the Women’s Health Initiative
Moorthi, S., Paguirigan, A. L., Itagi, P., Ko, M., Pettinger, M. B., Hoge, A. C. H., Nag, A., Patel, N. A., Wu, F., Sather, C. L., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.174643 · Cited by 21
“We also noted the enrichment of ATF7IP somatic mutations in tumors from smokers (3 of 17 [18”
Effect of smoking status on immunotherapy for lung cancer: a systematic review and meta-analysis
Luo, D., Yang, D., Cao, D., Gong, Z., He, F., Hou, Y., & Lin, S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1422160 · Cited by 22
“However, some limitations of these studies may weaken the reliability of their evidence; for example, some studies only recruited a small proportion of non-smokers, limiting the analysis (7, 8).”
BackgroundSato, Y., Okamoto, I., Kameyama, H., Kudoh, S., Saito, H., Sanada, M., Kudo, N., Wakimoto, J., Fujino, K., Ikematsu, Y., et al. (2020) · Diagnostics · doi:10.3390/diagnostics10110949 · Cited by 19
“The main risk factor for SCLC is smoking as more than 95% of SCLC patients are current or ex-smokers [3].”
BackgroundLou, J., Yang, Y., Gu, Q., Price, B. A., Qiu, Y., Fedoriw, Y. D., Desai, S., Mose, L. E., Chen, B., Tateishi, S., et al. (2021) · NAR Cancer · doi:10.1093/narcan/zcaa037 · Cited by 20
“We analyzed relationships between RAD18 and mutagenesis in the settings of LUAD and LUSC because exposure to genotoxic chemicals in cigarette smoke is a clear risk factor for these diseases (51).”
MethodHaratake, N., Hu, Q., Okamoto, T., Jogo, T., Toyokawa, G., Kinoshita, F., Takenaka, T., Tagawa, T., Iseda, N., Itoh, S., et al. (2021) · Annals of Surgery · doi:10.1097/sla.0000000000005001 · Cited by 19
“It has been reported that smoking increases the tumor mutational burden, cell-to-cell heterogeneity and driver mutations,(10) and there is a statistically significant positive correlation between the amount of smoking and the mutational burden.(9) On the other hand, our previous result showed that among SCC patients,…”
BackgroundResultIto, T., Kudoh, S., Fujino, K., Sanada, M., Tenjin, Y., Saito, H., Nakaishi-Fukuchi, Y., Kameyama, H., Ichimura, T., Udaka, N., et al. (2022) · ACTA HISTOCHEMICA ET CYTOCHEMICA · doi:10.1267/ahc.22-00031 · Cited by 19
Genomic analysis of early-stage lung cancer reveals a role for TP53 mutations in distant metastasis
Egeren, D. V., Kohli, K., Warner, J. L., Bedard, P. L., Riely, G. J., Lepisto, E. M., Schrag, D., Lenoue-Newton, M. L., Catalano, P. J., Kehl, K. L., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-21448-1 · Cited by 19
Zhao, W., Song, A., Xu, Y., Wu, Q., Liu, C., Yin, J. C., Ou, Q., Wu, X., Shao, Y. W., & Zhao, X. (2023) · BMC Medicine · doi:10.1186/s12916-023-02768-z · Cited by 19
Pizzutilo, E. G., Romanò, R., Roazzi, L., Agostara, A. G., Oresti, S., Zeppellini, A., Giannetta, L. G., Cerea, G., Signorelli, D., Siena, S., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-0161 · Cited by 20
Cai, H. “., & Wang, C. (2017) · CHEST Journal · doi:10.1016/j.chest.2017.06.030 · Cited by 19
Tobacco smoking, E-cigarettes, and nicotine harm
Harris, C. C. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1722636115 · Cited by 19
Stiborová, M., Dračínská, H., Bořek-Dohalská, L., Klusoňová, Z., Holecová, J., Martínková, M., Schmeiser, H. H., & Arlt, V. M. (2018) · Toxicology · doi:10.1016/j.tox.2018.04.001 · Cited by 19
“, 2008, 2012) and preferentially leads to the induction of G to T transversion mutations (Alexandrov et al., 2016; Kucab et al., 2015; Nik-Zainal et al., 2015).”
BackgroundWang, X., Zeng, Q., Li, Z., Yang, X. Y., Xia, W., & Chen, Z. (2019) · Thoracic Cancer · doi:10.1111/1759-7714.12976 · Cited by 18
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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