文章：

染色体碎裂和癌症：染色体碎裂的原因和后果

Chromothripsis and cancer: causes and consequences of chromosome shattering

原文发布日期：2012-09-13

DOI: 10.1038/nrc3352

类型: Review Article

开放获取: 否

要点：

1. Chromothripsis is a phenomenon by which tens to thousands of chromosomal rearrangements occur, with the available evidence indicating that chromothripsis can be generated by a single catastrophic event during the life history of a cell.
2. Rearrangements can occur by chromosome shattering and rejoining of pieces by end-joining DNA repair pathways, or by aberrant DNA replication-based mechanisms.
3. Chromothripsis may contribute to cellular transformation, as it occurs early in tumour development: end-joining-based repair can lead to the loss of tumour suppressor functions, oncogenic fusions and oncogene amplification via double-minute chromosomes. In addition, aberrant DNA replication mechanisms taking place during chromothripsis can lead to oncogene amplification.
4. An attractive model for the generation of chromothripsis invokes the involvement of micronuclei. According to this model, chromosomes contained within micronuclei suffer aberrant DNA replication and can then be pulverized in mitosis with subsequent rejoining of DNA segments leading to a derivative chromosome or chromosomes that can be reincorporated into the main nucleus. Chromothripsis is observed with a higher frequency in cells with mutated p53. This leads to a model in which micronuclei formation owing to chromosome segregation errors is allowed in p53-deficient cells, potentially yielding chromothripsis and the evolution of cancer. Defects in chromosome segregation and/or DNA damage response processes may also contribute to carcinogenesis by promoting chromothripsis.

要点翻译：

1. 染色体碎裂是一种可导致数十至数千种染色体重排的现象，现有证据表明该现象可能由细胞生命史中的单一灾难性事件引发。
2. 重排可通过染色体破碎及末端连接DNA修复途径实现片段重组，也可基于异常的DNA复制机制发生。
3. 染色体碎裂在肿瘤发生早期即出现，可能促进细胞转化：基于末端连接的修复会导致抑瘤功能丧失、致癌基因融合以及双微染色体介导的致癌基因扩增。此外，染色体碎裂过程中的异常DNA复制机制也可引发致癌基因扩增。
4. 一个引人注目的染色体碎裂形成模型涉及微核的参与。该模型认为，滞留在微核内的染色体会经历异常DNA复制，随后在有丝分裂过程中发生粉碎，DNA片段通过重组形成衍生染色体，最终被重新整合至主核内。在p53突变细胞中染色体碎裂的发生频率更高，由此推导出以下模型：p53缺陷细胞因染色体分离错误形成微核，进而可能引发染色体碎裂并推动癌症演进。染色体分离和/或DNA损伤应答过程的缺陷也可能通过促进染色体碎裂而参与癌变过程。

英文摘要：

Genomic alterations that lead to oncogene activation and tumour suppressor loss are important driving forces for cancer development. Although these changes can accumulate progressively during cancer evolution, recent studies have revealed that many cancer cells harbour chromosomes bearing tens to hundreds of clustered genome rearrangements. In this Review, we describe how this striking phenomenon, termed chromothripsis, is likely to arise through chromosome breakage and inaccurate reassembly. We also discuss the potential diagnostic, prognostic and therapeutic implications of chromothripsis in cancer.

摘要翻译： 

导致原癌基因激活和抑癌基因缺失的基因组改变是癌症发生的重要驱动力。尽管这些变化可在癌症演进过程中逐步积累，但近期研究发现，许多癌细胞携带着带有数十至数百个成簇基因组重排的染色体。在本综述中，我们描述了这种惊人现象——染色体碎裂（chromothripsis）——如何通过染色体断裂和错误重排产生。我们还探讨了染色体碎裂在癌症中的潜在诊断、预后及治疗意义。

原文链接：

Chromothripsis and cancer: causes and consequences of chromosome shattering