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

Latham A1, Srinivasan P1, Kemel Y1, Shia J1, Bandlamudi C1, Mandelker D1, Middha S1, Hechtman J1, Zehir A1, Dubard-Gault M1, Tran C1, Stewart C1, Sheehan M1, Penson A1, DeLair D1, Yaeger R1, Vijai J1, Mukherjee S1, Galle J1, Dickson MA1, Janjigian Y1, O'Reilly EM1, Segal N1, Saltz LB1, Reidy-Lagunes D1, Varghese AM1, Bajorin D1, Carlo MI1, Cadoo K1, Walsh MF1, Weiser M1, Aguilar JG1, Klimstra DS1, Diaz LA Jr1, Baselga J1, Zhang L1, Ladanyi M1, Hyman DM1, Solit DB1, Robson ME1, Taylor BS1, Offit K1, Berger MF1, Stadler ZK1.

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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.