Topography of mutational signatures in human cancer

The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome sequenced tumours from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features with signatures of related aetiologies being similarly affected. Certain signatures exhibit periodic behaviours or cancer-type specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via COSMIC, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer. ### Competing Interest Statement LBA is a compensated consultant and has equity interest in io9, LLC. His spouse is an employee of Biotheranostics, Inc. LBA is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. ENB and LBA declare provisional patent applications for "Clustered mutations for the treatment of cancer" (U.S. provisional application serial number 63/289,601) and "Artificial intelligence architecture for predicting cancer biomarker" (serial number 63/269,033). All other authors declare no competing interests.