Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion 1 , 2 . Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes. Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity.

中文翻译：

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普遍的病变分离塑造癌症基因组进化


癌症是通过获得致癌突变而产生的，并通过克隆扩增而生长 1, 2 。在这里，我们揭示了大多数诱变 DNA 损伤不会在单个细胞周期内分解为突变的 DNA 碱基对。相反，DNA损伤未修复地分离到子细胞中进行多个细胞世代，从而导致随后突变的染色体规模定相。我们在诱变剂诱导的小鼠肝脏肿瘤中描述了这一过程，并表明跨持续性病变的 DNA 复制可以在连续的细胞分裂中产生多个替代等位基因，从而产生多等位基因和组合遗传多样性。病变的定相能够准确测量链偏向修复过程、量化致癌选择以及精细绘制姐妹染色单体交换事件。最后，我们证明病变分离是外源诱变剂的统一特性，包括人类细胞和肿瘤中的紫外线和化疗药物，这对癌症基因组的进化和适应具有深远的影响。诸如引起癌症的突变损伤在细胞分裂过程中经常分离（未修复），导致多个等位基因在子代细胞中发生定相，从而导致肿瘤异质性。