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

    701 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

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


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