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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

39 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
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 - 8 Mar 2009
Externally published	Yes

Keywords

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

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10.1016/j.canlet.2008.10.009

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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

@article{2c8fae1764904e6d801bcbc48eae0aa8,

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.",

keywords = "Barrett's adenocarcinoma, Barrett's metaplasia, Carcinogenesis, Hypermethylation, O-methylguanine-DNA methyltransferase (MGMT)",

author = "Doerthe Kuester and Wa'el El-Rifai and Peng, \{Dun Fa\} and Petra Ruemmele and Ivonne Kroeckel and Brigitte Peters and Moskaluk, \{Christopher A.\} and Manfred Stolte and Klaus M{\"o}nkem{\"u}ller and Frank Meyer and Schulz, \{Hans Ulrich\} and Arndt Hartmann and Albert Roessner and Regine Schneider-Stock",

note = "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 K{\"u}gler for their skillful technical assistance.",

year = "2009",

month = mar,

day = "8",

doi = "10.1016/j.canlet.2008.10.009",

language = "English",

volume = "275",

pages = "117--126",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "Elsevier Ireland Ltd",

number = "1",

}

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

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 - https://www.scopus.com/pages/publications/58549106559

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 -

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

Abstract

Keywords

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