Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer

作者：Alicia J. Latham, Preethi Srinivasan, Yelena M. Kemel, Jinru Shia, Chaitanya Bandlamudi, Diana L. Mandelker, Sumit Middha, Jaclyn Frances Hechtman, Ahmet Zehir, Marianne E. Dubard-Gault, Christina Tran, Carolyn Stewart, Margaret R. Sheehan, Alexander V. Penson, Deborah F. DeLair, Rona D. Yaeger, Joseph Vijai, Semanti Mukherjee, Jesse Galle, Mark Andrew Dickson, Yelena Yuriy Janjigian, Eileen Mary O'Reilly, Neil Howard Segal, Leonard B. Saltz, Diane L. Reidy‐Lagunes, Anna M. Varghese, Dean F. Bajorin, Maria Isabel Carlo, Karen Anne Cadoo, Michael Francis Walsh, Martin R. Weiser, Julio García Aguilar, David S. Klimstra, Luis Alberto Diaz, José Baselga, Liying Zhang, Marc Ladanyi, David Michael Hyman, David B. Solit, Mark E. Robson, Barry S. Taylor, Kenneth Offit, Michael F. Berger, Zsofia Kinga Stadler · 发表于：Journal of Clinical Oncology · 年份：2018 · DOI：10.1200/jco.18.00283 · 被引用次数：637 · 研究领域：Genetic factors in colorectal cancer、Multiple and Secondary Primary Cancers、Cancer Immunotherapy and Biomarkers

PURPOSE: Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status. METHODS: MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed. RESULTS: Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic ...