Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus.
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.
Kuester
Doerthe
D
Department of Pathology, Otto-von-Guericke University Magdeburg, Germany.
El-Rifai
Wa'el
W
Peng
DunFa
D
Ruemmele
Petra
P
Kroeckel
Ivonne
I
Peters
Brigitte
B
Moskaluk
Christopher A
CA
Stolte
Manfred
M
Mönkemüller
Klaus
K
Meyer
Frank
F
Schulz
Hans-Ulrich
HU
Hartmann
Arndt
A
Roessner
Albert
A
Schneider-Stock
Regine
R
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*
D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes