TY - JOUR T1 - Mutational signatures associated with tobacco smoking in human cancer JF - bioRxiv DO - 10.1101/051417 SP - 051417 AU - Ludmil B. Alexandrov AU - Young Seok Ju AU - Kerstin Haase AU - Peter Van Loo AU - IƱigo Martincorena AU - Serena Nik-Zainal AU - Yasushi Totoki AU - Akihiro Fujimoto AU - Hidewaki Nakagawa AU - Tatsuhiro Shibata AU - Peter J. Campbell AU - Paolo Vineis AU - David H. Phillips AU - Michael R. Stratton Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/03/051417.abstract N2 - 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.ONE SENTENCE SUMMARY Multiple distinct mutational processes associate with tobacco smoking in cancer reflecting direct and indirect effects of tobacco smoke. ER -