Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types
Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types
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DOI：
10.1101/gr.255026.119
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发表时间：
2020-03-01
期刊：
影响因子：
7
通讯作者：
Nakagawa, Hidewaki
中科院分区：
文献类型：
--
作者：
Fujimoto, Akihiro;Fujita, Masashi;Nakagawa, Hidewaki
微卫星是1- 6-bp单位的重复序列，在人类基因组中已经发现了大约1000万个微卫星。微卫星易受DNA错配错误的影响，因此已被用于检测具有错配修复缺陷的癌症。为了揭示微卫星重复区域在基因组水平上的突变景观，我们分析了21种组织类型的2717个泛癌样本全基因组中的约201亿个微卫星。首先，我们开发了一个新的插入和删除调用程序（MIMcall），它考虑了不同类型的微卫星的错误模式。在2717个泛癌症样本中，我们的分析确定了31个样本，包括结直肠癌，子宫癌和胃癌，具有较高比例的突变微卫星（>= 0.03），我们将其定义为全基因组水平的微卫星不稳定性（MSI）癌症。接下来，我们发现了20个高度突变的微卫星，可用于高灵敏度地检测MSI癌症。第三，我们发现复制时间和DNA形状与微卫星突变率显著相关。最后，对错配修复基因突变的分析表明，体细胞SNV和短插入缺失比种系突变和结构变异具有更大的功能影响。我们的分析提供了一个全面的图片中的微卫星区域的突变，并揭示了突变的可能原因，以及MSI检测提供了一个有用的标记集。
Microsatellites are repeats of 1- to 6-bp units, and approximately 10 million microsatellites have been identified across the human genome. Microsatellites are vulnerable to DNA mismatch errors and have thus been used to detect cancers with mismatch repair deficiency. To reveal the mutational landscape of microsatellite repeat regions at the genome level, we analyzed approximately 20.1 billion microsatellites in 2717 whole genomes of pan-cancer samples across 21 tissue types. First, we developed a new insertion and deletion caller (MIMcall) that takes into consideration the error patterns of different types of microsatellites. Among the 2717 pan-cancer samples, our analysis identified 31 samples, including colorectal, uterus, and stomach cancers, with a higher proportion of mutated microsatellite (>= 0.03), which we defined as microsatellite instability (MSI) cancers of genome-wide level. Next, we found 20 highly mutated microsatellites that can be used to detect MSI cancers with high sensitivity. Third, we found that replication timing and DNA shape were significantly associated with mutation rates of microsatellites. Last, analysis of mutations in mismatch repair genes showed that somatic SNVs and short indels had larger functional impacts than germline mutations and structural variations. Our analysis provides a comprehensive picture of mutations in the microsatellite regions and reveals possible causes of mutations, as well as provides a useful marker set for MSI detection.