Landscape of Microsatellite Instability Across 39 Cancer Types.
Landscape of Microsatellite Instability Across 39 Cancer Types.
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DOI：
10.1200/po.17.00073
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发表时间：
2017
影响因子：
4.6
通讯作者：
Roychowdhury S
中科院分区：
文献类型：
--
作者：
Bonneville R;Krook MA;Kautto EA;Miya J;Wing MR;Chen HZ;Reeser JW;Yu L;Roychowdhury S
微卫星不稳定性（MSI）是发生在基因组微卫星上的一种超突变模式，由错配修复系统的缺陷引起。导致MSI的错配修复缺陷已在几种类型的人类癌症中得到充分描述，最常见于结直肠癌、子宫内膜癌和胃腺癌。MSI是已知的预测和预后，特别是在结直肠癌;然而，目前的临床指南只建议结直肠癌和子宫内膜癌的MSI测试。因此，在其他类型的癌症中，对MSI的患病率和程度知之甚少。使用我们最近发布的MSI调用软件MANTIS，我们分析了来自癌症基因组图谱和治疗适用研究的11，139个肿瘤-正常对的全外显子组数据，以产生有效的治疗项目和39种癌症类型的外部数据源。在这些癌症类型的子集内，我们评估了与MSI相关的突变负荷、突变特征和体细胞变异。我们在所有评估的癌症中发现了3.8%的MSI-存在于27种肿瘤类型中-最明显的是肾上腺皮质癌（ACC），宫颈癌（CESC）和间皮瘤，其中MSI尚未得到很好的描述。此外，观察到MSI高的ACC和CESC肿瘤比微卫星稳定的ACC和CESC肿瘤具有更高的平均突变负荷。我们提供了在几种类型的癌症中尚未被认识到的MSI的证据。这些发现支持临床MSI测试在多种癌症类型中的扩展作用，因为预计MSI阳性肿瘤患者将从临床试验中的新型免疫疗法中获益。
Microsatellite instability (MSI) is a pattern of hypermutation that occurs at genomic microsatellites and is caused by defects in the mismatch repair system. Mismatch repair deficiency that leads to MSI has been well described in several types of human cancer, most frequently in colorectal, endometrial, and gastric adenocarcinomas. MSI is known to be both predictive and prognostic, especially in colorectal cancer; however, current clinical guidelines only recommend MSI testing for colorectal and endometrial cancers. Therefore, less is known about the prevalence and extent of MSI among other types of cancer. Using our recently published MSI-calling software, MANTIS, we analyzed whole-exome data from 11,139 tumor-normal pairs from The Cancer Genome Atlas and Therapeutically Applicable Research to Generate Effective Treatments projects and external data sources across 39 cancer types. Within a subset of these cancer types, we assessed mutation burden, mutational signatures, and somatic variants associated with MSI. We identified MSI in 3.8% of all cancers assessed—present in 27 of tumor types—most notably adrenocortical carcinoma (ACC), cervical cancer (CESC), and mesothelioma, in which MSI has not yet been well described. In addition, MSI-high ACC and CESC tumors were observed to have a higher average mutational burden than microsatellite-stable ACC and CESC tumors. We provide evidence of as-yet-unappreciated MSI in several types of cancer. These findings support an expanded role for clinical MSI testing across multiple cancer types as patients with MSI-positive tumors are predicted to benefit from novel immunotherapies in clinical trials.