Process-specific somatic mutation distributions vary with three-dimensional genome structure

Somatic mutationsarise during the life history of a cell. Mutationsoccurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutationsthroughout the neoplastic process and during cancer evolution. Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations. Understanding the underlying factors generating somatic mutationsis crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timingand chromatin modifications are associated with variations in mutationaldensity. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutationalprocesses share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organizationand specific individual mutationalprocesses, we report here a study of 3000 tumor-normal pair whole genome datasets from more than 40 different human cancer types. Our analyses revealed that different mutationalprocesses lead to distinct somatic mutationdistributions between chromatin folding domains. APOBEC- or MSI-related mutationsare enriched in transcriptionally-active domains while mutationsoccurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutationalprocesses dictate the mutationdistributions in cancer genomes, and we show that mutationaldistributions shift during cancer evolution upon mutationalprocesses switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosomeleads to distinct somatic mutationdistribution on X chromosomein females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organizationand active mutationalprocesses has a substantial influence on the large-scale mutationrate variations observed in human cancer.