RT Journal Article
SR Electronic
T1 Process-specific somatic mutation distributions vary with three-dimensional genome structure
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 426080
DO 10.1101/426080
A1 Kadir C. Akdemir
A1 Victoria T. Le
A1 Sarah Killcoyne
A1 Devin A. King
A1 Ya-Ping Li
A1 Yanyan Tian
A1 Akira Inoue
A1 Samir Amin
A1 Frederick S. Robinson
A1 Rafael E. Herrera
A1 Erica J. Lynn
A1 Kin Chan
A1 Sahil Seth
A1 Leszek J. Klimczak
A1 Moritz Gerstung
A1 Dmitry A. Gordenin
A1 John O’Brien
A1 Lei Li
A1 Roel G. Verhaak
A1 Peter Campbell
A1 Rebecca Fitzgerald
A1 Ashby J. Morrison
A1 Jesse R. Dixon
A1 P. Andrew Futreal
YR 2018
UL http://biorxiv.org/content/early/2018/10/14/426080.abstract
AB 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.