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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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“For instance, smoking results 76 mainly in C>A transitions in lung cancers, while ultraviolet (UV) radiation leaves a footprint involving 77 CC>TT dinucleotide substitutions in skin cancers [7, 14].”
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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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