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

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. Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations. Understanding the underlying causes of mutations is critical for developing potential preventions and tailoring the clinical treatments. Earlier studies have revealed that DNA replication timing and chromatin modifications are associated with variations in mutational density. In order to understand the interplay between spatial genome organization and individual mutational processes, we report here a study of more than 3000 whole genome datasets from 50 different cancer studies. 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 and ultraviolet (UV) light exposure or a gastric flux-related mutational signature (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, therefore mutational distributions could 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120166 | GEO | 2020/07/01

REPOSITORIES: GEO

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Project description:International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not been identified by conventional epidemiology yet potentially make a substantial contribution to cancer burden1. This pertains to clear cell renal cell carcinoma (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence2. Some carcinogens generate somatic mutations and a complementary strategy for detecting past exposures is to sequence the genomes of cancers from populations with different incidence rates and infer underlying causes from differences in patterns of somatic mutations. Here, we sequenced 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in >70% cases and <2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher kidney cancer incidence rates (p-value <6 × 10−18). Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, geographically variable, mutagenic exposures potentially affecting 10s of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics. Linked cross omic data sets:Geographic variation of mutagenic exposures in kidney cancer genomes – patient metadata files (Mutographs) associated with this study are available in the European Genome-Phenome Archive: https://ega-archive.org/datasets/EGAD00001012223.

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

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