Reliable Pan-Cancer Microsatellite Instability Assessment by Using Targeted Next-Generation Sequencing Data

作者：Sumit Middha, Liying Zhang, Khédoudja Nafa, Gowtham Jayakumaran, Donna Wong, Hyunjae Ryan Kim, Justyna Sadowska, Michael F. Berger, Deborah F. DeLair, Jinru Shia, Zsofia Kinga Stadler, David S. Klimstra, Marc Ladanyi, Ahmet Zehir, Jaclyn Frances Hechtman · 发表于：JCO Precision Oncology · 年份：2017 · DOI：10.1200/po.17.00084 · 被引用次数：389 · 研究领域：Genetic factors in colorectal cancer、Cancer Genomics and Diagnostics、Cancer Immunotherapy and Biomarkers

PURPOSE: 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. METHODS: 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. RESULTS: 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 corre...