Abstract 40: Mutation of EPCAM gene is less frequent in Korean and EPCAM immunohistochemistry can identify Lynch syndrome in patients who do not meet Bethesda criteria.

Abstract

Lynch syndrome is an inherited tumor predisposition syndrome caused by germline mutations of DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Recently, germline deletions affecting the epithelial cell adhesion molecule (EPCAM) gene located upstream of MSH2 were identified as a novel mutational mechanism causing Lynch syndrome. However, most studies were conducted in western populations, where the incidence of CRC is high. To identify the incidence of germline deletions of EPCAM gene in Korea where the incidence of CRC is relatively low and socioeconomic condition is different, we conducted a comprehensive study in 4,993 patients diagnosed and treated with CRCs at a single institute between 2006 and 2011. In all tumor samples, microsatellite instability (MSI) test and immunohistochemistry (IHC) for MMR proteins were performed. In cases with loss of MLH1 protein, methylation of MLH1 by MethyLight was performed and cases with hypermethylation of MLH1 gene were excluded. Germline mutations of MLH1, MSH2 and MSH6 were performed in patients who fulfilled at least one of the revised Bethesda criteria. In 97 patients with loss of MSH2 protein, EPCAM IHC and multiplex ligation-dependent probe amplification for germline deletions of the EPCAM and MSH2 gene were performed. Loss of expression of MMR proteins and/or MSI-high was observed in 337 (6.7%) patients, 112 (2.2%) patients met revised Bethesda criteria, and 54 (1.1%) patients harbored germline mutations of MMR genes. Out of 97 MSH2-negative CRCs, 5 (5.2%) showed concomitant loss of EPCAM expression and EPCAM exon 9 deletionmutations. Out of 5 cases with EPCAM mutation and protein loss, four patients showed familial histories of CRCs. However, one patient showed no family history. In this patient, although multiple liver metastases were the first manifestation, he lived 6 more years after diagnosis. In this large single study cohort, we found that 5.2% of MSH2-negative CRCs were caused by EPCAM deletion mutations, which is lower than previously reported incidences in western populations. Moreover, we could find one candidate patient with de novo mutation of EPCAM gene, which has not been reported yet. Our results strongly support that in routine screening of patients with CRC for Lynch syndrome, a simple and sensitive EPCAM IHC should be included even in cases do not meet Bethesda criteria.

Citation Format: So Young Kang, Shin Woo Kang, In-Gu Do, Dong Kyung Chang, Kyoung M. Kim. Mutation of EPCAM gene is less frequent in Korean and EPCAM immunohistochemistry can identify Lynch syndrome in patients who do not meet Bethesda criteria. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 40. doi:10.1158/1538-7445.AM2013-40