The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors

Abstract

Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage. Modern Pathology (2012) 25, 911-916;

Identification of a Japanese Lynch syndrome patient with large deletion in the 3′ region of theEPCAMgene

“…However, somatic events involved in inactivation of the remaining allele of MSH2 have heretofore not been fully characterized. Huth et al (17) reported that four out of six various cancers that developed in LS patients with germline EPCAM deletions revealed homozygous EPCAM deletion in cancer tissue. On the other hand, a recent study by Spaepen et al (7) reported that one colorectal cancer developed in an LS patient with a large 4 Mb deletion including the EPCAM, MSH2 and MSH6 genes, while the other showed homozygous deletion of only the EPCAM gene.…”

A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome

“…9 As a result, an indicative FH would lead to further investigations in the event of no MMR mutation being found in a proband; such investigations are not included in the model. l Constitutional epimutations may not be detected by current methods, 273,274 and though at present they would be included in the model as negative diagnostic test results (with LS possibly being assumed on the basis of FH), it is possible that in the future further testing may be recommended for such mutations which could incur extra costs and affect cost-effectiveness. However, a doubling of the cost of diagnostic genetic testing did not have a significant impact on cost-effectiveness, except for strategy 8 (universal genetic testing).…”

Colorectal cancer in a 9-year-old due to combinedEPCAMandMSH2germline mutations: case report of a unique genotype and immunophenotype

“…As far as we are aware, there have been no previous reports of this combination of gene mutations resulting in early onset colorectal cancer. The transcription of a mutated copy of EPCAM has been reported to result in downstream silencing of the adjacent MSH2 gene through transcriptional read-through 1. Immunohistochemistry in this case elegantly shows that complete absence of MSH2 expression can occur when one MSH2 allele is mutated, and the second allele is silenced with transcription of mutated copy of EPCAM .…”

“…Rarely, LS can also arise due to germline deletion of the 3′ region of the epithelial cell adhesion molecule ( EPCAM ) gene, an event that results in silencing of the in cis downstream MSH2 gene in epithelial cells 1 2. As with other causes of LS, EPCAM mutations have been associated with increased risk of colorectal and endometrial carcinomas 3…”