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

Kadir C. Akdemir, Victoria T. Le, Sarah Killcoyne, Devin A. King, Ya-Ping Li, Yanyan Tian, Akira Inoue, Samir Amin, Frederick S. Robinson, Rafael E. Herrera, Erica J. Lynn, Kin Chan, Sahil Seth, Leszek J. Klimczak, Moritz Gerstung, Dmitry A. Gordenin, John O’Brien, Lei Li, Roel G. Verhaak, Peter Campbell, Rebecca Fitzgerald, Ashby J. Morrison, Jesse R. Dixon, P. Andrew Futreal
doi: https://doi.org/10.1101/426080
Kadir C. Akdemir
1The Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
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Victoria T. Le
2Salk Institute for Biological Studies, La Jolla, CA, USA
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Sarah Killcoyne
3MRC Cancer Unit, Hutchison/MRC Research Center, University of Cambridge, Cambridge, UK
4European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK
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Devin A. King
5Department of Biology, Stanford University, Stanford, CA, USA
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Ya-Ping Li
6Department of Ophthalmology and Visual Sciences, McGovern Medical School, University of Texas Health Sciences Center at Houston, Houston, TX
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Yanyan Tian
7Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
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Akira Inoue
1The Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
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Samir Amin
8The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
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Frederick S. Robinson
1The Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
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Rafael E. Herrera
5Department of Biology, Stanford University, Stanford, CA, USA
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Erica J. Lynn
7Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
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Kin Chan
9Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences and Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institute of Health, NC, USA
10Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada
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Sahil Seth
1The Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
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Leszek J. Klimczak
9Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences and Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institute of Health, NC, USA
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Moritz Gerstung
4European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK
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Dmitry A. Gordenin
9Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences and Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institute of Health, NC, USA
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John O’Brien
6Department of Ophthalmology and Visual Sciences, McGovern Medical School, University of Texas Health Sciences Center at Houston, Houston, TX
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Lei Li
7Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
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Roel G. Verhaak
8The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
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Peter Campbell
11Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridge, UK
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Rebecca Fitzgerald
3MRC Cancer Unit, Hutchison/MRC Research Center, University of Cambridge, Cambridge, UK
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Ashby J. Morrison
5Department of Biology, Stanford University, Stanford, CA, USA
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Jesse R. Dixon
2Salk Institute for Biological Studies, La Jolla, CA, USA
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P. Andrew Futreal
1The Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
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  • For correspondence: afutreal@mdanderson.org
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Abstract

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 14, 2018.
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Process-specific somatic mutation distributions vary with three-dimensional genome structure
Kadir C. Akdemir, Victoria T. Le, Sarah Killcoyne, Devin A. King, Ya-Ping Li, Yanyan Tian, Akira Inoue, Samir Amin, Frederick S. Robinson, Rafael E. Herrera, Erica J. Lynn, Kin Chan, Sahil Seth, Leszek J. Klimczak, Moritz Gerstung, Dmitry A. Gordenin, John O’Brien, Lei Li, Roel G. Verhaak, Peter Campbell, Rebecca Fitzgerald, Ashby J. Morrison, Jesse R. Dixon, P. Andrew Futreal
bioRxiv 426080; doi: https://doi.org/10.1101/426080
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Process-specific somatic mutation distributions vary with three-dimensional genome structure
Kadir C. Akdemir, Victoria T. Le, Sarah Killcoyne, Devin A. King, Ya-Ping Li, Yanyan Tian, Akira Inoue, Samir Amin, Frederick S. Robinson, Rafael E. Herrera, Erica J. Lynn, Kin Chan, Sahil Seth, Leszek J. Klimczak, Moritz Gerstung, Dmitry A. Gordenin, John O’Brien, Lei Li, Roel G. Verhaak, Peter Campbell, Rebecca Fitzgerald, Ashby J. Morrison, Jesse R. Dixon, P. Andrew Futreal
bioRxiv 426080; doi: https://doi.org/10.1101/426080

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