TY - JOUR
T1 - Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus
AU - Kuester, Doerthe
AU - El-Rifai, Wa'el
AU - Peng, Dun Fa
AU - Ruemmele, Petra
AU - Kroeckel, Ivonne
AU - Peters, Brigitte
AU - Moskaluk, Christopher A.
AU - Stolte, Manfred
AU - Mönkemüller, Klaus
AU - Meyer, Frank
AU - Schulz, Hans Ulrich
AU - Hartmann, Arndt
AU - Roessner, Albert
AU - Schneider-Stock, Regine
N1 - Funding Information:
This study was supported in part by financial support for a “Spitzenbonusprojekt” of the Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany (institutional grant to the Department of Pathology, Magdeburg) and by the National Cancer Institute Grant R01CA106176 (WER). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute, Vanderbilt University or University of Magdeburg. The authors thank Dr. Michael Vieth (Department of Pathology, Bayreuth, Germany) for his assistance in verifying the histopathological diagnosis and support in marking the lesions of interest on hematoxylin-eosin-stained sections. The authors are grateful to Simone Staeck, Hiltraud Scharfenort, Nadine Wiest, Claudia Miethke and Carola Kügler for their skillful technical assistance.
PY - 2009/3/8
Y1 - 2009/3/8
N2 - 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.
AB - 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.
KW - Barrett's adenocarcinoma
KW - Barrett's metaplasia
KW - Carcinogenesis
KW - Hypermethylation
KW - O-methylguanine-DNA methyltransferase (MGMT)
UR - http://www.scopus.com/inward/record.url?scp=58549106559&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2008.10.009
DO - 10.1016/j.canlet.2008.10.009
M3 - Article
C2 - 19027227
AN - SCOPUS:58549106559
SN - 0304-3835
VL - 275
SP - 117
EP - 126
JO - Cancer Letters
JF - Cancer Letters
IS - 1
ER -