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Mutational signatures associated with tobacco smoking in human cancer

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

Posted 03 May 2016
bioRxiv DOI: 10.1101/051417 (published DOI: 10.1126/science.aag0299)

Tobacco smoking increases the risk of at least 15 classes of cancer. We analyzed somatic mutations and DNA methylation in 5,243 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 clock-like mutational process. 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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