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Introduction The Adenomatous Polyposis Coli (APC) protein plays a pivotal role in the regulation of β-catenin, which is linked to the intracellular part of the cell-cell adhesion molecule E-cadherin. Reduced or absent expression of this essential protein in maintenance of tissue architecture, is associated with aggressive histopathological characteristics such as increased tumor invasiveness and metastasis, leading to the hypothesis that E-cadherin is a tumor suppressor gene. Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by a germline mutation in the APC gene. It is characterized by numerous adenomatous colorectal polyps that will progress to adenocarcinoma. The duodenum is the main site for (pre-) malignant extra-colonic manifestations in FAP patients. The prevalence of the mainly peri-ampullary adenomas varies from 50 - 90%, whereas in 2-5 % of the FAP patients, duodenal carcinomas have been detected. Compared to the general population the risk of duodenal adenocarcinoma is exceptionally high. Aim The aim of the current study is to evaluate possible causes of the predisposition to develop duodenal adenomas in FAP by characterizing the distribution of E-cadherin and β-catenin in adenomas and normal duodenum of FAP patients compared with sporadic duodenal adenomas and normal non-FAP duodenum. Materials & methods Normal FAP duodenum (n = 13) and duodenal adenomas (n = 50, total 26 patients) were compared with sporadic duodenal adenomas (n = 7) and normal non-FAP duodenum (n = 15), by immunohistochemical staining for extracellular E-cadherin (HECD-1), intracellular E-cadherin (clone 36) and β-catenin (clone 14). The loss of E-cadherin was scored on a four-point scale. β-catenin was scored for membranous, cytoplasmic or nuclear expression. Results Whereas the intracellular component of E-cadherin was present in all cases, a significant loss of extracellular E-cadherin was observed in both FAP and sporadic duodenal adenomas (52% and 42% respectively). This loss of expression was also seen in the morphological normal duodenum of FAP patients (54% versus 6 % normal non-FAP duodenum, p = 0.01). Cytoplasmatic localization of β-catenin was observed in the FAP adenomas, all other samples showed both membranous and nuclear expression. Conclusion Already in the normal duodenum of FAP patients loss of extracellular E-cadherin is observed, whereas the loss in non-FAP patients is first observed in the adenoma stage, suggesting that the high susceptibility for (pre-) malignant transformation of the FAP duodenum might be caused by loss of E-cadherin.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]