Mutations in human cells exhibit increased burden in heterochromatic, late DNA replication time (RT) chromosomal domains, with variation in mutation rates between tissues mirroring variation in heterochromatin and RT. We observed that regional mutation risk further varies between individual tumors in a manner independent of cell type, identifying three signatures of domain-scale mutagenesis in >4,000 tumor genomes. The major signature reflects remodeling of heterochromatin and of the RT program domains seen across tumors, tissues and cultured cells, and is robustly linked with higher expression of cell proliferation genes. Regional mutagenesis is associated with loss of activity of the tumor-suppressor genes RB1 and TP53, consistent with their roles in cell cycle control, with distinct mutational patterns generated by the two genes. Loss of regional heterogeneity in mutagenesis is associated with deficiencies in various DNA repair pathways. These mutation risk redistribution processes modify the mutation supply towards important genes, diverting the course of somatic evolution.

人类细胞中的突变表现出异染色质晚期 DNA 复制时间 (RT) 染色体结构域的负担增加，组织之间突变率的变化反映了异染色质和 RT 的变化。我们观察到，各个肿瘤之间的区域突变风险以独立于细胞类型的方式进一步变化，在超过 4,000 个肿瘤基因组中识别出域规模突变的三个特征。主要特征反映了肿瘤、组织和培养细胞中可见的异染色质和 RT 程序域的重塑，并且与细胞增殖基因的较高表达密切相关。区域突变与肿瘤抑制基因RB1和TP53的活性丧失相关，这与它们在细胞周期控制中的作用一致，并且这两个基因产生不同的突变模式。诱变中区域异质性的丧失与各种 DNA 修复途径的缺陷有关。这些突变风险重新分配过程改变了重要基因的突变供应，改变了体细胞进化的进程。