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首页> 美国卫生研究院文献>The Journal of Molecular Diagnostics : JMD >A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability–High Cases in 67000 Patient Samples
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A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability–High Cases in 67000 Patient Samples

机译：一种新的下一代测序方法用于检测67000例患者样品中1000微卫星不稳定性高案的微卫星不稳定性和泛肿瘤表征

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Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.
机译：微卫星不稳定性（MSI）是用于预测对免疫检查点抑制剂疗法的反应的重要生物标志物，因为最近的MSI-HIGH（MSI-H）实体肿瘤的检查点抑制剂批准强调。在此，我们描述并验证使用福尔马林固定的石蜡包埋的样品从下一代测序综合基因组分析测定中确定MSI状态的新方法。该方法是97％（65/67）一致，具有目前的标准，PCR和免疫组化。我们进一步将该方法应用于> 67,000名患者肿瘤样品以鉴定富含MSI-稳定或MSI-H肿瘤群的基因和途径。数据表明，尽管结直肠癌和子宫内膜癌以外的肿瘤罕见，但MSI-H样品存在于许多肿瘤类型中。此外，大型样本集显示，MSI-H肿瘤在多种常见途径中选择性地共享基因的改变，包括WNT，磷脂酰肌醇3-激酶和缺口。最后，MSI足够，但没有必要，用于肿瘤突变负担升高。因此，可以从综合基因组分布中以高精度确定MSI，从而允许在所有肿瘤类型上进行高效的MSI-H检测，尤其是由于MSI的罕见发病率，常规使用免疫组织化学或基于PCR基测定的常规使用。 MSI-H肿瘤在特定信号传导途径的改变中富集，提供了用于研究指导的免疫检查点抑制剂治疗与途径靶向疗法的基本原理。

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