Middha Sumit, Zhang Liying, Nafa Khedoudja, Jayakumaran Gowtham, Wong Donna, Kim Hyunjae R, Sadowska Justyna, Berger Michael F, Delair Deborah F, Shia Jinru, Stadler Zsofia, Klimstra David S, Ladanyi Marc, Zehir Ahmet, Hechtman Jaclyn F
Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precis Oncol. 2017;2017. doi: 10.1200/PO.17.00084. Epub 2017 Oct 3.
Microsatellite instability (MSI)/mismatch repair (MMR) status is increasingly important in the management of patients with cancer to predict response to immune checkpoint inhibitors. We determined MSI status from large-panel clinical targeted next-generation sequencing (NGS) data across various solid cancer types.
The MSI statuses of 12,288 advanced solid cancers consecutively sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical NGS assay were inferred by using MSIsensor, a program that reports the percentage of unstable microsatellites as a score. Cutoff score determination and sensitivity/specificity were based on MSI polymerase chain reaction (PCR) and MMR immunohistochemistry.
By using an MSIsensor score ≥ 10 to define MSI high (MSI-H), 83 (8%) of 996 colorectal cancers (CRCs) and 42 (16%) of 260 uterine endometrioid cancers (UECs) were MSI-H. Validation against MSI PCR and/or MMR immunohistochemistry performed for 138 (24 MSI-H, 114 microsatellite stable [MSS]) CRCs, and 40 (15 MSI-H, 25 MSS) UECs showed a concordance of 99.4%. MSIsensor also identified 68 MSI-H/MMR-deficient (MMR-D) non-CRC/UECs. Of 9,591 non-CRC/UEC tumors with MSS MSIsensor status, 456 (4.8%) had slightly elevated scores(≥3 and <10) of which 96.6% with available material were confirmed to be MSS by MSI PCR. MSI-H was also detected and confirmed in three non-CRC/UECs with low exonic mutation burden (< 20). MSIsensor correctly scored all 15 polymerase ε ultra-mutated cancers as negative for MSI.
MSI status can be reliably inferred by MSIsensor from large-panel targeted NGS data. Concurrent MSI testing by NGS is resource efficient, is potentially more sensitive for MMR-D than MSI PCR, and allows identification of MSI-H across various cancers not typically screened, as highlighted by the finding that 35% (68 of 193) of all MSI-H tumors were non-CRC/ UEC.
微卫星不稳定性（MSI）/错配修复（MMR）状态在癌症患者管理中对于预测免疫检查点抑制剂的反应越来越重要。我们从针对各种实体癌类型的大型临床靶向新一代测序（NGS）数据中确定了MSI状态。
使用MSIsensor程序推断12288例连续进行纪念斯隆凯特琳癌症中心可操作癌症靶点综合突变分析临床NGS检测的晚期实体癌的MSI状态，该程序将不稳定微卫星的百分比作为一个分数报告。临界值分数的确定以及敏感性/特异性基于MSI聚合酶链反应（PCR）和MMR免疫组织化学。
使用MSIsensor分数≥10定义为高度微卫星不稳定（MSI-H），996例结直肠癌（CRC）中有83例（8%）以及260例子宫内膜样癌（UEC）中有42例（16%）为MSI-H。对138例CRC（24例MSI-H，114例微卫星稳定[MSS]）和40例UEC（15例MSI-H，25例MSS）进行MSI PCR和/或MMR免疫组织化学验证，一致性为99.4%。MSIsensor还鉴定出68例MSI-H/错配修复缺陷（MMR-D）的非CRC/UEC。在9591例MSS MSIsensor状态的非CRC/UEC肿瘤中，456例（4.8%）分数略有升高（≥3且<10），其中96.6%有可用材料的经MSI PCR确认为MSS。在3例低外显子突变负担（<20）的非CRC/UEC中也检测并确认了MSI-H。MSIsensor正确地将所有15例聚合酶ε超突变癌症评分为MSI阴性。
MSIsensor可以从大型靶向NGS数据中可靠地推断MSI状态。通过NGS进行同步MSI检测资源高效，对于MMR-D可能比MSI PCR更敏感，并且能够识别各种通常未筛查的癌症中的MSI-H，所有MSI-H肿瘤中有35%（193例中的68例）为非CRC/UEC这一发现突出了这一点。
