TY - JOUR T1 - Process-specific somatic mutation distributions vary with three-dimensional genome structure JF - bioRxiv DO - 10.1101/426080 SP - 426080 AU - Kadir C. Akdemir AU - Victoria T. Le AU - Sarah Killcoyne AU - Devin A. King AU - Ya-Ping Li AU - Yanyan Tian AU - Akira Inoue AU - Samir Amin AU - Frederick S. Robinson AU - Rafael E. Herrera AU - Erica J. Lynn AU - Kin Chan AU - Sahil Seth AU - Leszek J. Klimczak AU - Moritz Gerstung AU - Dmitry A. Gordenin AU - John O’Brien AU - Lei Li AU - Roel G. Verhaak AU - Peter Campbell AU - Rebecca Fitzgerald AU - Ashby J. Morrison AU - Jesse R. Dixon AU - P. Andrew Futreal Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/10/14/426080.abstract N2 - Somatic mutations arise during the life history of a cell. Mutations occurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutations throughout the neoplastic process and during cancer evolution (Martincorena and Campbell, 2015). Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations (Zhang and Pellman, 2015). Understanding the underlying factors generating somatic mutations is crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timing (Stamatoyannopoulos et al., 2009) and chromatin modifications (Schuster-Böckler and Lehner, 2012) are associated with variations in mutational density. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutational processes share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organization and specific individual mutational processes, 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 mutational processes lead to distinct somatic mutation distributions between chromatin folding domains. APOBEC- or MSI-related mutations are enriched in transcriptionally-active domains while mutations occurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, and we show that mutational distributions shift during cancer evolution upon mutational processes switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosome leads to distinct somatic mutation distribution on X chromosome in females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancer. ER -