Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer.

ABSTRACT

BACKGROUND: Endoglin (ENG) is a 180-kilodalton transmembrane glycoprotein that functions as a component of the transforming growth factor-ß receptor complex. Recently, ENG promoter hypermethylation was reported in several human cancers. METHODS: The authors examined ENG promoter hypermethylation using real-time, quantitative, methylation-specific polymerase chain reaction in 260 human esophageal tissues. RESULTS: ENG hypermethylation demonstrated highly discriminative receiver operating characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P<.01). It is interesting to note that ENG normalized methylation values were significantly higher in ESCC compared with normal tissue (P<.01) or EAC (P<.01). The ENG hypermethylation frequency was 46.2% in ESCC and 11.9% in normal esophageal tissue, but increased early and sequentially during EAC-associated neoplastic progression to 13.3% in Barrett metaplasia (BE), 25% in dysplastic BE, and 26.9% in frank EAC. ENG hypermethylation was significantly higher in normal esophageal tissue from patients with ESCC (mean, 0.0186) than in normal tissue from patients with EAC (mean, 0.0117; P<.05). Treatment of KYSE220 ESCC cells with the demethylating agent 5-aza-2'-deoxycytidine was found to reverse ENG methylation and reactivate ENG mRNA expression. CONCLUSIONS: Promoter hypermethylation of ENG appears to be a frequent, tissue-specific event in human ESCC and exhibits a field defect with promising biomarker potential for the early detection of ESCC. In addition, ENG hypermethylation occurs in a subset of human EAC, and early during BE-associated esophageal neoplastic progression.