title: Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus.
abstract: To determine the relevance of MGMT in Barrett's carcinogenesis, we analyzed promotor hypermethylation and expression of MGMT in Barrett's adenocarcinomas and its paired precursor lesions from 133 patients using a methylation-specific PCR, real-time RT-PCR and immunohistochemistry. Hypermethylation was detected in 78.9% of esophageal adenocarcinomas, in 100% of Barrett's intraepithelial neoplasia, in 88.9% of Barrett's metaplasia, but only in 21.4% of normal esophageal mucosa samples (P<0.001) and correlated significantly with downregulation of MGMT transcripts (P=0.048) and protein expression (P=0.02). Decrease of protein expression was significantly correlated with progressed stage of disease, lymph node invasion and tumor size. We conclude, that aberrant promoter methylation of MGMT is a frequent and early event during tumorigenesis of Barrett's esophagus. High prevalence of MGMT hypermethylation may represent a candidate marker for improved diagnosis and targeted therapy in Barrett's adenocarcinoma.
authors.affiliation: Department of Pathology, Otto-von-Guericke University Magdeburg, Germany.
authors.forename: Doerthe
authors.initials: D
authors.lastname: Kuester
authors.forename: Wa'el
authors.initials: W
authors.lastname: El-Rifai
authors.forename: DunFa
authors.initials: D
authors.lastname: Peng
authors.forename: Petra
authors.initials: P
authors.lastname: Ruemmele
authors.forename: Ivonne
authors.initials: I
authors.lastname: Kroeckel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Peters
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.forename: Manfred
authors.initials: M
authors.lastname: Stolte
authors.forename: Klaus
authors.initials: K
authors.lastname: Mönkemüller
authors.forename: Frank
authors.initials: F
authors.lastname: Meyer
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schulz
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes