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

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.

体细胞突变在细胞的生命历程中产生。发生在癌症驱动基因中的突变可能最终导致临床上可检测到的疾病的发展。新生的癌症谱系在肿瘤形成过程以及癌症演化过程中持续获得体细胞突变（马丁科雷纳和坎贝尔，2015年）。外在和内源性诱变因素导致这些体细胞突变的积累（张和佩尔曼，2015年）。了解产生体细胞突变的潜在因素对于制定潜在的预防、治疗和临床决策至关重要。早期研究表明，DNA复制时间（斯塔马托扬诺普洛斯等人，2009年）和染色质修饰（舒斯特 - 博克勒和莱纳，2012年）与突变密度的变化有关。然而，从这些早期研究中不清楚的是，驱动体细胞突变过程的所有外在和外源性因素是否与染色质状态和结构具有相似的关系。为了理解空间基因组组织与特定个体突变过程之间的相互作用，我们在此报告了一项对来自40多种不同人类癌症类型的3000个肿瘤 - 正常配对全基因组数据集的研究。我们的分析表明，不同的突变过程导致染色质折叠结构域之间体细胞突变分布不同。APOBEC或微卫星不稳定性（MSI）相关突变在转录活跃结构域富集，而由于烟草烟雾、紫外线（UV）照射或病因不明的特征（特征17）导致的突变主要在转录不活跃结构域富集。活跃的突变过程决定了癌症基因组中的突变分布，并且我们表明在突变过程转换时，癌症演化过程中突变分布会发生变化。此外，人类中一种极端染色质结构的显著例子，即失活X染色体的独特折叠模式，导致在各种癌症类型中女性X染色体上的体细胞突变分布与男性不同。总体而言，三维基因组组织与活跃突变过程之间的相互作用对在人类癌症中观察到的大规模突变率变化具有重大影响。