期刊
SCIENCE
卷 354, 期 6312, 页码 618-622出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aag0299
关键词
-
资金
- Wellcome Trust [098051, WT100183MA, WT088340MA, FC001202, 101126/Z/13/Z, 101126/B/13/Z]
- GRAIL
- J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory
- U.S. Department of Energy (DOE) National Nuclear Security Administration [DE-AC52-06NA25396]
- National Nuclear Security Administration of the DOE
- Francis Crick Institute - Cancer Research UK [FC001202]
- UK MRC [FC001202]
- Cancer Research UK [C313/A14329]
- National Institute for Health Research (NIHR) Health Protection Research Unit in Health Impact of Environmental Hazards at King's College London
- PHE
- European Commission [308610-FP7]
- Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development [15ck0106094h0002]
- National Cancer Center Research and Development Funds [26-A-5]
- Cancer Research UK [14329] Funding Source: researchfish
- The Francis Crick Institute [10202] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [26430196] Funding Source: KAKEN
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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