A genome-wide view of microsatellite instability: old stories of cancer mutations revisited with new sequencing technologies.
A genome-wide view of microsatellite instability: old stories of cancer mutations revisited with new sequencing technologies.
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DOI：
10.1158/0008-5472.can-14-1225
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发表时间：
2014-11-15
期刊：
影响因子：
11.2
通讯作者：
Park PJ
中科院分区：
文献类型：
--
作者：
Kim TM;Park PJ
微卫星是简单的串联重复序列，存在于人类基因组的数百万个基因座上。微卫星不稳定性(MSI)是指当DNA错配修复系统存在缺陷时，在癌症基因组中频繁发生的微卫星上的DNA滑动事件。这些体细胞突变可导致肿瘤抑制基因失活或扰乱其他非编码调控序列，从而在癌症发生中发挥作用。在这里，我们将讨论高通量测序数据如何促进基因组或外显子组范围的发现，以及更详细地研究微卫星不稳定的癌症基因组中的MSI事件。我们将讨论这种方法的方法论方面，并强调从癌症基因组图谱项目最近对结直肠癌和子宫内膜癌基因组的分析中获得的见解。这些包括识别肿瘤类型内和跨肿瘤的新的MSI靶点，以及MSI事件的可能性与染色质结构之间的关系。鉴于癌症基因组外显子组和基因组测序的日益普及，MSI的全面表征可能成为癌症进化的一个有价值的标记，并有助于寻找治疗靶点。
Microsatellites are simple tandem repeats that are present at millions of loci in the human genome. Microsatellite instability (MSI) refers to DNA slippage events on microsatellites that occur frequently in cancer genomes when there is a defect in the DNA mismatch repair system. These somatic mutations can result in inactivation of tumor suppressor genes or disrupt other non-coding regulatory sequences, thereby playing a role in carcinogenesis. Here, we will discuss the ways in which high-throughput sequencing data can facilitate a genome- or exome-wide discovery and more detailed investigation of MSI events in microsatellite-unstable cancer genomes. We will address the methodological aspects of this approach and highlight insights from recent analyses of colorectal and endometrial cancer genomes from The Cancer Genome Atlas project. These include identification of novel MSI targets within and across tumor types and the relationship between the likelihood of MSI events to chromatin structure. Given the increasing popularity of exome and genome sequencing of cancer genomes, a comprehensive characterization of MSI may serve as a valuable marker of cancer evolution and aid in a search for therapeutic targets.