The University of Tennessee Health Science Center and West Cancer Center, Memphis, Tennessee.
Caris Life Sciences, Phoenix, Arizona.
Cancer Med. 2018 Mar;7(3):746-756. doi: 10.1002/cam4.1372. Epub 2018 Feb 13.
Microsatellite instability (MSI) testing identifies patients who may benefit from immune checkpoint inhibitors. We developed an MSI assay that uses data from a commercially available next-generation sequencing (NGS) panel to determine MSI status. The assay is applicable across cancer types and does not require matched samples from normal tissue. Here, we describe the MSI-NGS method and explore the relationship of MSI with tumor mutational burden (TMB) and PD-L1. MSI examined by PCR fragment analysis and NGS was compared for 2189 matched cases. Mismatch repair status by immunohistochemistry was compared to MSI-NGS for 1986 matched cases. TMB was examined by NGS, and PD-L1 was determined by immunohistochemistry. Among 2189 matched cases that spanned 26 cancer types, MSI-NGS, as compared to MSI by PCR fragment analysis, had sensitivity of 95.8% (95% confidence interval [CI] 92.24, 98.08), specificity of 99.4% (95% CI 98.94, 99.69), positive predictive value of 94.5% (95% CI 90.62, 97.14), and negative predictive value of 99.2% (95% CI, 98.75, 99.57). High MSI (MSI-H) status was identified in 23 of 26 cancer types. Among 11,348 cases examined (including the 2189 matched cases), the overall rates of MSI-H, TMB-high, and PD-L1 positivity were 3.0%, 7.7%, and 25.4%, respectively. Thirty percent of MSI-H cases were TMB-low, and only 26% of MSI-H cases were PD-L1 positive. The overlap between TMB, MSI, and PD-L1 differed among cancer types. Only 0.6% of the cases were positive for all three markers. MSI-H status can be determined by NGS across cancer types. MSI-H offers distinct data for treatment decisions regarding immune checkpoint inhibitors, in addition to the data available from TMB and PD-L1.
微卫星不稳定性 (MSI) 检测可确定可能受益于免疫检查点抑制剂的患者。我们开发了一种使用商业可用的下一代测序 (NGS) 面板数据来确定 MSI 状态的 MSI 检测方法。该方法适用于多种癌症类型，并且不需要来自正常组织的匹配样本。在这里，我们描述了 MSI-NGS 方法，并探讨了 MSI 与肿瘤突变负担 (TMB) 和 PD-L1 的关系。对 2189 对匹配病例进行了 PCR 片段分析和 NGS 检测的 MSI 检查。对 1986 对匹配病例进行了免疫组化检测错配修复状态与 MSI-NGS 的比较。通过 NGS 检测 TMB，通过免疫组化检测 PD-L1。在跨越 26 种癌症类型的 2189 对匹配病例中，与 PCR 片段分析相比，MSI-NGS 的灵敏度为 95.8%(95%置信区间[CI]92.24,98.08)，特异性为 99.4%(95%CI98.94,99.69)，阳性预测值为 94.5%(95%CI90.62,97.14)，阴性预测值为 99.2%(95%CI98.75,99.57)。在 26 种癌症类型中的 23 种中发现了高 MSI(MSI-H)状态。在 11348 例检查病例中(包括 2189 对匹配病例)，MSI-H、TMB-高和 PD-L1 阳性的总体发生率分别为 3.0%、7.7%和 25.4%。30%的 MSI-H 病例为 TMB-低，只有 26%的 MSI-H 病例为 PD-L1 阳性。TMB、MSI 和 PD-L1 之间的重叠在癌症类型之间存在差异。只有 0.6%的病例同时对这三种标志物呈阳性。MSI-H 状态可以通过 NGS 在多种癌症类型中确定。除了 TMB 和 PD-L1 提供的数据外，MSI-H 还为免疫检查点抑制剂的治疗决策提供了独特的数据。
