Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer.
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Latham Alicia, Srinivasan Preethi, Kemel Yelena, Shia Jinru, Bandlamudi Chaitanya, Mandelker Diana, Middha Sumit, Hechtman Jaclyn, Zehir Ahmet, Dubard-Gault Marianne, Tran Christina, Stewart Carolyn, Sheehan Margaret, Penson Alexander, DeLair Deborah, Yaeger Rona, Vijai Joseph, Mukherjee Semanti, Galle Jesse, Dickson Mark A, Janjigian Yelena, O'Reilly Eileen M, Segal Neil, Saltz Leonard B, Reidy-Lagunes Diane, Varghese Anna M, Bajorin Dean, Carlo Maria I, Cadoo Karen, Walsh Michael F, Weiser Martin, Aguilar Julio Garcia, Klimstra David S, Diaz Luis A, Baselga Jose, Zhang Liying, Ladanyi Marc, Hyman David M, Solit David B, Robson Mark E, Taylor Barry S, Offit Kenneth, Berger Michael F, Stadler Zsofia K
Аннотация
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 testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases.
CONCLUSION: MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.