Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus

Doerthe Kuester; Wa'el El-Rifai; Dun Fa 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

doi:10.1016/j.canlet.2008.10.009

Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus

Doerthe Kuester, Wa'el El-Rifai, Dun Fa 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

Surgery

Research output: Contribution to journal › Article

28 Scopus citations

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.

Original language	English (US)
Pages (from-to)	117-126
Number of pages	10
Journal	Cancer letters
Volume	275
Issue number	1
DOIs	https://doi.org/10.1016/j.canlet.2008.10.009
State	Published - Mar 8 2009

Keywords

Barrett's adenocarcinoma
Barrett's metaplasia
Carcinogenesis
Hypermethylation
O-methylguanine-DNA methyltransferase (MGMT)

ASJC Scopus subject areas

Oncology
Cancer Research

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Kuester, D., El-Rifai, W., Peng, D. F., Ruemmele, P., Kroeckel, I., Peters, B., Moskaluk, C. A., Stolte, M., Mönkemüller, K., Meyer, F., Schulz, H. U., Hartmann, A., Roessner, A., & Schneider-Stock, R. (2009). Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus. Cancer letters, 275(1), 117-126. https://doi.org/10.1016/j.canlet.2008.10.009

Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus. / Kuester, Doerthe; El-Rifai, Wa'el ; Peng, Dun Fa; Ruemmele, Petra; Kroeckel, Ivonne; Peters, Brigitte; Moskaluk, Christopher A.; Stolte, Manfred; Mönkemüller, Klaus; Meyer, Frank; Schulz, Hans Ulrich; Hartmann, Arndt; Roessner, Albert; Schneider-Stock, Regine.

In: Cancer letters, Vol. 275, No. 1, 08.03.2009, p. 117-126.

Research output: Contribution to journal › Article

Kuester, D, El-Rifai, W , Peng, DF, Ruemmele, P, Kroeckel, I, Peters, B, Moskaluk, CA, Stolte, M, Mönkemüller, K, Meyer, F, Schulz, HU, Hartmann, A, Roessner, A & Schneider-Stock, R 2009, 'Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus', Cancer letters, vol. 275, no. 1, pp. 117-126. https://doi.org/10.1016/j.canlet.2008.10.009

Kuester, Doerthe ; El-Rifai, Wa'el ; Peng, Dun Fa ; Ruemmele, Petra ; Kroeckel, Ivonne ; Peters, Brigitte ; Moskaluk, Christopher A. ; Stolte, Manfred ; Mönkemüller, Klaus ; Meyer, Frank ; Schulz, Hans Ulrich ; Hartmann, Arndt ; Roessner, Albert ; Schneider-Stock, Regine. / Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus. In: Cancer letters. 2009 ; Vol. 275, No. 1. pp. 117-126.

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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.",

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AU - Kroeckel, Ivonne

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AU - Moskaluk, Christopher A.

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AU - Mönkemüller, Klaus

AU - Meyer, Frank

AU - Schulz, Hans Ulrich

AU - Hartmann, Arndt

AU - Roessner, Albert

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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.

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