小柯机器人

广泛病灶分离影响癌症基因组进化
2020-06-28 13:44

英国爱丁堡大学Martin S. Taylor及其研究小组的最新研究发现广泛的病灶分离影响癌症基因组进化。相关论文在线发表在2020年6月24日出版的《自然》杂志上。

研究人员发现大多数诱变性DNA损伤不能在单个细胞周期内分解为突变的DNA碱基对。取而代之的是,未修复的DNA损伤分离至多个细胞的子细胞中,从而导致后续突变的染色体水平定相。

研究人员在诱变剂诱导的小鼠肝癌模型中验证了这一过程,并表明跨代持续存在的病变DNA复制可以在连续的细胞分裂过程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。病变定相能够准确测量偏向链的修复过程、量化致癌选择并精确绘制姐妹染色单体互换事件。

最后,研究人员证明了在人类细胞和肿瘤中,病变隔离是外源性诱变剂(包括紫外线和化学治疗剂)的统一特性,对癌症基因组的进化和适应具有深远的影响。

研究人员表示,癌症是由致癌突变引起的,并通过克隆扩增生长。

附:英文原文

Title: Pervasive lesion segregation shapes cancer genome evolution

Author: Sarah J. Aitken, Craig J. Anderson, Frances Connor, Oriol Pich, Vasavi Sundaram, Christine Feig, Tim F. Rayner, Margus Lukk, Stuart Aitken, Juliet Luft, Elissavet Kentepozidou, Claudia Arnedo-Pac, Sjoerd V. Beentjes, Susan E. Davies, Ruben M. Drews, Ailith Ewing, Vera B. Kaiser, Ava Khamseh, Erika Lpez-Arribillaga, Aisling M. Redmond, Javier Santoyo-Lopez, Ins Sents, Lana Talmane, Andrew D. Yates, Colin A. Semple, Nria Lpez-Bigas, Paul Flicek, Duncan T. Odom, Martin S. Taylor

Issue&Volume: 2020-06-24

Abstract: 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.

DOI: 10.1038/s41586-020-2435-1

Source: https://www.nature.com/articles/s41586-020-2435-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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