Pervasive lesion segregation shapes cancer genome evolution.
Pervasive lesion segregation shapes cancer genome evolution.
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DOI：
10.1038/s41586-020-2435-1
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发表时间：
2020-07-01
期刊：
影响因子：
64.8
通讯作者：
Taylor, Martin S
中科院分区：
文献类型：
--
作者：
Aitken, Sarah J;Anderson, Craig J;Taylor, Martin S
癌症通过获得致癌突变而产生，并通过克隆扩增而生长1，2。在这里，我们揭示了大多数致突变DNA损伤在单个细胞周期内不会分解为突变的DNA碱基对。相反，DNA损伤分离，未修复，进入多个细胞代的子细胞，导致后续突变的染色体规模定相。我们在诱变剂诱导的小鼠肝肿瘤中表征了这一过程，并表明持续病变的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。病变的定相使得能够准确测量链偏向修复过程、量化致癌选择和精细绘制姐妹染色单体交换事件。最后，我们证明，病变隔离是一个统一的属性的外源性诱变剂，包括紫外线和化疗药物在人体细胞和肿瘤，这对癌症基因组的进化和适应具有深远的影响。
Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. 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.