TY - JOUR T1 - Sequence dependencies and mutation rates of localized mutational processes in cancer JF - bioRxiv DO - 10.1101/2021.10.27.465848 SP - 2021.10.27.465848 AU - Gustav Alexander Poulsgaard AU - Simon Grund Sørensen AU - Randi Istrup Juul AU - Morten Muhlig Nielsen AU - Jakob Skou Pedersen Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/28/2021.10.27.465848.abstract N2 - Background Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show strong sequence and regional preferences. As a result, some sequence contexts mutate at much higher rates than others. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes.Results We analyze the mutation rates of all 11-mer genomic sequence contexts using the PCAWG set of 2,583 pan-cancer whole genomes. We further associate individual mutations and contexts to mutational signatures and estimate their relative mutation rates. We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate increases further when focusing on certain genomic regions, such as signature 62 in poised promoters, where the mutation is increased several thousand folds over the overall data set average.Conclusion We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.Competing Interest StatementThe authors have declared no competing interest. ER -