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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.
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