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Frequent Hypermethylation of the 5' CpG Island of E-Cadherin in Esophageal Adenocarcinoma

University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 [P. G. C., F. F.]; Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [E. I. H., R. H., A. A. F., J. G. H.]; and Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205 [T-T. W.]

Purpose: E-cadherin, a M_r 120,000 transmembrane glycoprotein, mediates calcium-dependent intercellular adhesion that is essential for normal tissue homeostasis. Loss of E-cadherin occurs in a variety of epithelial tumors and is correlated with invasion and metastasis. In esophageal adenocarcinoma, reduction of E-cadherin expression has been demonstrated previously, but mutations of the gene (CDH1) are rare.

Experimental Design: In this study, we used a nested PCR approach to examine the methylation status of the 5' CpG island of E-cadherin in esophageal specimens obtained from individuals with and without a history of esophageal cancer.

Results: In four individuals without esophageal cancer, E-cadherin was completely unmethylated in normal squamous cell-lined esophageal mucosa. In contrast, in patients with esophageal adenocarcinoma, E-cadherin was methylated in 26 of 31 (84%) tumor specimens. In the majority of cases, matched normal tissue (esophagus or stomach) from each patient was completely unmethylated. By immunostaining, methylated tumor samples demonstrated heterogeneously decreased membranous E-cadherin staining.

Conclusions: These data suggest that epigenetic silencing via aberrant methylation of the E-cadherin promoter is a common cause of inactivation of this gene in esophageal adenocarcinoma.

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