Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).

中文翻译：

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体细胞微卫星插入缺失分析可识别人类肿瘤中的驱动事件。

微卫星 (MS) 是短 DNA 基序的可变长度重复序列，以重复基序的插入或缺失 (indels) 形式表现出高突变率。尽管它们普遍存在，但由于在短读长测序数据中难以检测到它们，体细胞 MS indels 对癌症的贡献在很大程度上尚未得到探索。在这里，我们提出了两个工具：MSMuTect，用于准确检测体细胞 MS indels，和 MSMutSig，用于识别包含 MS indels 的基因，其频率高于偶然预期的频率。将 MSMuTect 应用于代表 20 种肿瘤类型的 6,747 个人类肿瘤的全外显子组数据，我们在癌症基因中发现了超过 1,000 个以前未描述的 MS 插入缺失。此外，我们证明 MS indels 的数量和模式可以准确地区分微卫星稳定肿瘤和微卫星不稳定性肿瘤，从而有可能改善临床相关亚组的分类。最后，我们确定了 7 个 MS indel 驱动热点：4 个位于已知癌症基因（ACVR2A、RNF43、JAK1 和 MSH3）中，3 个位于先前未涉及癌症驱动的基因（ESRP1、PRDM2 和 DOCK3）。