RT Journal Article
SR Electronic
T1 Mutational signatures associated with tobacco smoking in human cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 051417
DO 10.1101/051417
A1 Ludmil B. Alexandrov
A1 Young Seok Ju
A1 Kerstin Haase
A1 Peter Van Loo
A1 Iñigo Martincorena
A1 Serena Nik-Zainal
A1 Yasushi Totoki
A1 Akihiro Fujimoto
A1 Hidewaki Nakagawa
A1 Tatsuhiro Shibata
A1 Peter J. Campbell
A1 Paolo Vineis
A1 David H. Phillips
A1 Michael R. Stratton
YR 2016
UL http://biorxiv.org/content/early/2016/05/03/051417.abstract
AB 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.