Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review

Abstract

Lynch syndrome (clinically referred to as HNPCC - Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3'end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition.

Figure 1

The frequency of mismatch repair gene mutations in Lynch syndrome.

Figure 2

A pedigree familiar to Lynch syndrome. COL, colon cancer; FGT, cancer of the female genital tract; d. - age of death.

Figure 3

Schematic representation of signaling pathways involving EPCAM, proposed by Maetzel D et al. (2009)[23]. (a) Cleavage of EPCAM by TACE and PS-2. (b)EPCAM signalling and possible cross-talk with E-cadherin and Wnt pathways. EPCAM signalling is induced by RIP, leading to EpICD nuclear translocation in a complex with FHL2 and -catenin. Within the nucleus, the EpICD complex interacts with Lef-1 and contacts DNA. Upon interference with E-cadherin, EPCAM may increase the availability of its interaction partner -catenin in the soluble fraction. Cross-talk with the Wnt pathway is conceivable at the level of -catenin and Lef-1 interactions with EpICD, and is known for induction of the EPCAM promoter by Tcf4 (Maetzel D, Denzel S, Mack B, et al., Nature Cell Biology 11, 162 – 171, 2009).