LAUSR

Significance Mutational signatures have emerged as essential tools in cancer genomics, providing clinically relevant insights as well as accurate background models needed when assessing signals of selection in cancer. Here, we observe that the mutational signature of ultraviolet (UV) light varies across chromatin states, highlighting a previously unappreciated aspect of mutational signatures. Our results imply that locally derived, rather than genome-wide or exome-wide, signatures are more accurate, which is of relevance in situations such as cancer driver gene detection, where correct modelling of signatures and expected mutation rates is critical. We also show that incorporation of longer contextual patterns into the signature further improves modeling of UV mutations. Mutational signatures can reveal properties of underlying mutational processes and are important when assessing signals of selection in cancer. Here, we describe the sequence characteristics of mutations induced by ultraviolet (UV) light, a major mutagen in several human cancers, in terms of extended (longer than trinucleotide) patterns as well as variability of the signature across chromatin states. Promoter regions display a distinct UV signature with reduced TCG > TTG transitions, and genome-wide mapping of UVB-induced DNA photoproducts (pyrimidine dimers) showed that this may be explained by decreased damage formation at hypomethylated promoter CpG sites. Further, an extended signature model encompassing additional information from longer contextual patterns improves modeling of UV mutations, which may enhance discrimination between drivers and passenger events. Our study presents a refined picture of the UV signature and underscores that the characteristics of a single mutational process may vary across the genome.