title: Early involvement of death-associated protein kinase promoter hypermethylation in the carcinogenesis of Barrett's esophageal adenocarcinoma and its association with clinical progression.
abstract: Esophageal Barrett's adenocarcinoma (BA) develops through a multistage process, which is associated with the transcriptional silencing of tumor-suppressor genes by promoter CpG island hypermethylation. In this study, we explored the promoter hypermethylation and protein expression of proapoptotic death-associated protein kinase (DAPK) during the multistep Barrett's carcinogenesis cascade. Early BA and paired samples of premalignant lesions of 61 patients were analyzed by methylation-specific polymerase chain reaction and immunohistochemistry. For the association of clinicopathological markers and protein expression, an immunohistochemical tissue microarray analysis of 66 additional BAs of advanced tumor stages was performed. Hypermethylation of DAPK promoter was detected in 20% of normal mucosa, 50% of Barrett's metaplasia, 53% of dysplasia, and 60% of adenocarcinomas, and resulted in a marked decrease in DAPK protein expression (P < .01). The loss of DAPK protein was significantly associated with advanced depth of tumor invasion and advanced tumor stages (P < .001). Moreover, the severity of reflux esophagitis correlated significantly with the hypermethylation rate of the DAPK promoter (P < .003). Thus, we consider DAPK inactivation by promoter hypermethylation as an early event in Barrett's carcinogenesis and suggest that a decreased protein expression of DAPK likely plays a role in the development and progression of BA.
authors.affiliation: Department of Pathology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Doerthe
authors.initials: D
authors.lastname: Kuester
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Moskaluk
authors.forename: Sabine
authors.initials: S
authors.lastname: Krueger
authors.forename: Frank
authors.initials: F
authors.lastname: Meyer
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.forename: Manfred
authors.initials: M
authors.lastname: Stolte
authors.forename: Peter
authors.initials: P
authors.lastname: Malfertheiner
authors.forename: Hans
authors.initials: H
authors.lastname: Lippert
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D001471:Barrett Esophagus / Q000150:complications* / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D018899:CpG Islands; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004942:Esophagitis, Peptic / Q000209:etiology / Q000235:genetics; D005260:Female; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D046888:Tissue Array Analysis
chemical_list: D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases