LAUSR

Gynecologic cancers are routinely screened for DNA mismatch repair (MMR) gene mutations using immunohistochemistry (IHC) and/or PCR for MSI (microsatellite instability) to enable selection of immune checkpoint inhibitor therapy and screen for Lynch syndrome. The limited data that compares IHC and MSI in endometrial tumors has shown discordance rates of 5-10%. We reviewed MMR/MSI results in gynecologic cancers and used next generation sequencing (NGS) to interrogate discrepancies. Of the 328 cases with both IHC and MSI results, 256 (78.0%) were microsatellite stable (MSS) with preserved MMR (pMMR), 64 (19.5%) cases were MSI-H with dMMR, 2 cases showed subclonal loss of MLH1 and PMS2 with MSI-H and 6 cases were discordant. Overall, there was a 98.2% (322/328) IHC/MSI concordance. Discordant cases were re-tested and/or subject to NGS. Of the six discrepant cases, five showed dMMR with MSS and one showed pMMR with MSI-H. One dMMR/MSI-L case showed loss of PMS2 with a germline pathogenic mutation. The pMMR/MSI-H case was found to harbor pathogenic variants in MLH1 and MSH6. One of the two cases with subclonal populations demonstrated MSI-H in the dMMR area and MSS in the pMMR area. These results emphasize the importance of selecting the appropriate tumor tissue for both IHC and molecular testing and demonstrate that NGS can help resolve discrepant MMR and MSI results.