Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure

Kadir C. Akdemir, Victoria T. le, Justin M. Kim, Sarah Killcoyne, Devin A. King, Ya-Ping Lin, Yanyan Tian, Akira Inoue, Samirkumar B. Amin, Frederick S. Robinson, Manjunath Nimmakayalu, Rafael E. Herrera, Erica J. Lynn, Kin Chan, Sahil Seth, Leszek J. Klimczak, Moritz Gerstung, Dmitry A. Gordenin, John O’Brien, Lei LiYonathan Lissanu Deribe, Roel G. Verhaak, Peter J. Campbell, Rebecca Fitzgerald, Ashby J. Morrison, Jesse R. Dixon, P. Andrew Futreal

Research output: Contribution to journalArticleAcademicpeer-review

58 Citations (Scopus)


Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor–normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. 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 cancers.
Original languageEnglish
Pages (from-to)1178-1188
JournalNature Genetics
Issue number11
Publication statusPublished - 1 Nov 2020
Externally publishedYes

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