Mutational signatures associated with tobacco smoking in human cancer

Somatic mutations and DNA methylation were analysed 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, contributing to different extents in different cancers. One of these, found mainly 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. Smoking is associated with only limited differences in methylation. The results support the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence is lacking for some smoking-related cancer types.