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.

驱动基因的体细胞突变可能最终导致癌症的发生。因此，了解体细胞突变如何在癌症基因组中积累以及产生体细胞突变的潜在因素对于开发新的治疗策略至关重要。为了了解空间基因组组织和特定突变过程之间的相互作用，我们研究了来自 42 种不同人类癌症类型的 3,000 个肿瘤-正常对全基因组数据集。我们的分析表明，癌症基因组中体细胞突变负荷的变化与拓扑关联域边界共定位。与复制计时测量相比，域边界构成了更好的代理来跟踪突变负载变化。我们表明，不同的突变过程导致不同的体细胞突变分布，其中某些过程在活性域中产生突变，而其他过程在非活性域中产生突变。总体而言，三维基因组组织和活跃突变过程之间的相互作用对人类癌症中观察到的大规模突变率变化具有重大影响。