Mutational signatures associated with tobacco smoking in human cancer

Ludmil B. Alexandrov*, Young Seok Ju, Kerstin Haase, Peter Van Loo, Iñigo Martincorena, Serena Nik-Zainal, Yasushi Totoki, Akihiro Fujimoto, Hidewaki Nakagawa, Tatsuhiro Shibata, Peter J. Campbell, Paolo Vineis, David H. Phillips, Michael R. Stratton

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

595 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)618-622
Number of pages5
Issue number6312
Publication statusPublished - 4 Nov 2016

Bibliographical note

Funding Information:
This work was supported by the Wellcome Trust (grant 098051). S.N.-Z. is a Wellcome-Beit Prize Fellow and is supported through a Wellcome Trust Intermediate Fellowship (grant WT100183MA). P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant WT088340MA). M.R.S. is a paid advisor for GRAIL, a company developing technologies for sequencing of circulating tumor DNA for the purpose of early cancer detection. L.B.A. is personally supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. This research used resources provided by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the U.S. Department of Energy (DOE) National Nuclear Security Administration under contract no. DE-AC52-06NA25396. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the DOE. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (grant FC001202), the UK MRC (grant FC001202), and the Wellcome Trust (grant FC001202). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support toward the establishment of The Francis Crick Institute. D.H.P. is funded by Cancer Research UK (grant C313/A14329), the Wellcome Trust (grants 101126/Z/13/Z and 101126/B/13/Z), the National Institute for Health Research (NIHR) Health Protection Research Unit in Health Impact of Environmental Hazards at King's College London in partnership with PHE [the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, or PHE], and by the project EXPOSOMICS (grant agreement 308610-FP7) (European Commission). P.V. was partially supported by the project EXPOSOMICS (grant agreement 308610-FP7) (European Commission). Y.T. and T.S. are supported by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development (grant 15ck0106094h0002) and National Cancer Center Research and Development Funds (26-A-5). We thank The Cancer Genome Atlas, the International Cancer Genome Consortium, and the authors of all studies cited in table S1 for providing free access to their somatic mutational data.

Publisher Copyright:
Copyright © 2016 by the American Association for the Advancement of Science.


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