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: Doerthe Kuester, Wa'el El-Rifai, DunFa Peng, Petra Ruemmele, Ivonne Kroeckel, Brigitte Peters, Christopher A Moskaluk, Manfred Stolte, Klaus Mönkemüller, Frank Meyer, Hans-Ulrich Schulz, Arndt Hartmann, Albert Roessner, Regine Schneider-Stock
• Journal: Cancer letters (Cancer Lett) Vol. 275 Issue 1 Pg. 117-26 (Mar 08 2009) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 19027227 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes

Topics

• Adenocarcinoma (genetics, metabolism)
• Adult
• Aged
• Barrett Esophagus (genetics, metabolism)
• Carcinoma (genetics, metabolism)
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Disease Progression
• Female
• Gene Silencing
• Humans
• Lymphatic Metastasis
• Male
• Metaplasia (genetics, metabolism)
• Middle Aged
• Neoplasm Invasiveness
• Tumor Suppressor Proteins (genetics)