Many processes can cause the same nucleotide change in a genome, making the identification of the mechanisms causing mutations a difficult challenge. Here, we show that clustered mutations provide a more precise fingerprint of mutagenic processes. Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking. An additional signature matches the spectrum of translesion DNA polymerase eta (POLH). In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation. In solid tumors, however, they are associated with UV exposure and alcohol consumption and target the H3K36me3 chromatin of active genes in a mismatch repair (MMR)-dependent manner. These regions normally have a low mutation rate because error-free MMR also targets H3K36me3 chromatin. Carcinogens and error-prone repair therefore redistribute mutations to the more important regions of the genome, contributing a substantial mutation load in many tumors, including driver mutations.

This work was supported by grants from the ERC (616434), MINECO (BFU2011-26206 and SEV-2012-0208), AXA Research Fund (AXA Chair in Risk Prediction in Age-related Diseases), Bettencourt Schueller Foundation, AGAUR (2014 SGR 831), FP7 (projects 4DCellFate 277899, MAESTRA ICT-2013-612944, and InnoMol FP7-REGPOT-2012-2013-1-316289), the EMBL-CRG Systems Biology Program, and the CERCA program