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Absence of E-Cadherin Expression Distinguishes Noncohesive from Cohesive Pancreatic Cancer

Authors' Affiliations: Departments of ¹ Oncology, ² Surgery, and ³ Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Scott E. Kern, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, 1650 Orleans Street, 451 Cancer Research Building, Baltimore, MD 21231. Phone: 410-614-3316; Fax: 443-287-4653; E-mail: skern1{at}jhmi.edu.

Purpose: The role of E-cadherin in carcinogenesis is of great interest, but few studies have examined its relevance to pancreatic carcinoma.

Experimental Design: We evaluated E-cadherin protein expression by immunohistochemistry in pancreatobiliary cancers having a noncohesive histologic phenotype (21 undifferentiated adenocarcinomas and 7 signet ring carcinomas), comparing the results with pancreatic cancers having a cohesive phenotype (25 moderately differentiated and 14 poorly differentiated adenocarcinomas).

Results: Twenty of 21 undifferentiated cancers had complete absence of E-cadherin expression, as did two signet ring carcinomas. In contrast, cohesive cancers (n = 39) had E-cadherin labeling at the plasma membrane (P < 0.001). Subsets of cancers were also evaluated for β-catenin expression. All of the cohesive lesions (n = 28) showed a membranous β-catenin expression pattern, whereas noncohesive foci (n = 7) were characterized by either cytoplasmic labeling or complete absence of β-catenin protein expression, suggestive of a deficient zonula adherens in noncohesive cancers. E-cadherin promoter hypermethylation was observed in an undifferentiated pancreatic cancer cell line, MiaPaCa-2, whereas two pancreatic cancer cell lines derived from differentiated lesions lacked any evidence of E-cadherin promoter methylation. No pattern of E-cadherin promoter methylation could be determined in three primary cancers having mixed histologic patterns (contained both cohesive and noncohesive foci). No somatic mutations in E-cadherin were identified in noncohesive pancreatic cancers having inactivated E-cadherin.

Conclusions: Noncohesive pancreatic cancers were characterized by the loss of E-cadherin protein expression. Promoter hypermethylation is a possible mechanism of E-cadherin gene silencing in a subset of these cancers.