Synapse - Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer

Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer Journal Article

Authors:	Latham, A.; Srinivasan, P.; Kemel, Y.; Shia, J.; Bandlamudi, C.; Mandelker, D.; Middha, S.; Hechtman, J.; Zehir, A.; Dubard-Gault, M.; Tran, C.; Stewart, C.; Sheehan, M.; Penson, A.; DeLair, D.; Yaeger, R.; Vijai, J.; Mukherjee, S.; Galle, J.; Dickson, M. A.; Janjigian, Y.; O’Reilly, E. M.; Segal, N.; Saltz, L. B.; Reidy-Lagunes, D.; Varghese, A. M.; Bajorin, D.; Carlo, M. I.; Cadoo, K.; Walsh, M. F.; Weiser, M.; Aguilar, J. G.; Klimstra, D. S.; Diaz, L. A. Jr; Baselga, J.; Zhang, L.; Ladanyi, M.; Hyman, D. M.; Solit, D. B.; Robson, M. E.; Taylor, B. S.; Offit, K.; Berger, M. F.; Stadler, Z. K.
Article Title:	Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer
Abstract:	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 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. © 2018 by American Society of Clinical Oncology.
Journal Title:	Journal of Clinical Oncology
Volume:	37
Issue:	4
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2019-02-01
Start Page:	286
End Page:	295
Language:	English
DOI:	10.1200/jco.18.00283
PUBMED:	30376427
PROVIDER:	scopus
PMCID:	PMC6553803
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060753728&doi=10.1200%2fJCO.18.00283&partnerID=40&md5=9848a8da17c2f27f7a3944084865410a
Notes:	Article -- Export Date: 1 March 2019 -- Source: Scopus