491PD - Lynch-Like Syndrome: Characterization and Comparison with Epcam Deletion Carriers

Abstract

ABSTRACT Introduction: Colorectal cancers (CRCs) with MSI+ but without detectable germline mutation or hypermethylation in DNA mismatch repair (MMR) genes can be classified as Lynch-like Syndrome (LLS). The underlying mechanism and clinical significances of LLS are largely unknown. Methods: We measured MSI and MMR protein expression in 4,765 consecutive CRC cases. Among these, MSI+ cases were further classified based on clinical parameters, sequencing of MMR genes or polymerase e (POLE) and d (POLD1) and promoter methylation analysis of MLH1 and MSH2. Results: We found that MSI+ and MMR protein deficient CRCs comprised 6.3% (N = 302) of this cohort. Based on germline sequencing of 124 cases, we identified 54 LS with MMR germline mutation (LS-MMR), 15 LS with EPCAM deletions (LS-EPCAM) and 55 LLS patients. Of the 55 LLS patients, six (10.9%) had variants of unknown significance in the genes tested, and one patient had a novel somatic mutation (p.S459P) in POLE. In patients with biallelic deletions of EPCAM, all tumors and their matched normal mucosa showed promoter hypermethylation of MSH2. Conclusion: We found that patients with LLS and LS-EPCAM shared clinical features that differed from LS-MMR patients, including lower frequency of fulfillment of the revised Bethesda guidelines (83.6% and 86.7% vs. 98.1% for LS-MMR) and older mean age at CRC diagnosis (52.6 and 52.7 years vs. 43.9 years for LS-MMR). The similarity between LLS and LS-EPCAM suggests LLS as a subset of familial MSI+ CRC. Disclosure: All authors have declared no conflicts of interest.