© Copyright 2009 by the Society for Neuro-Oncology
Received May 15, 2008
Accepted August 13, 2008
Basic and Translational Investigations
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Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas
Sibille Everhard 1*,
Jörg Tost 2,
Hafida El abdalaoui 2,
Emmanuelle Crinière 1,
Florence Busato 2,
Yannick Marie 1,
Ivo G. Gut 2,
Marc Sanson 3,
Karima Mokhtari 4,
Florence Laigle-Donadey 3,
Khê Hoang-Xuan 3,
Jean-Yves Delattre 3,
Joëlle Thillet 5
1 INSERM, Paris, France; Université Pierre & Marie Curie, Faculté de médecine Pitié Salpétrière, Paris, France
2 Laboratory for Epigenetics, Centre National de Génotypage, CEA - Institut de Génomique, Evry, France
3 INSERM, Paris, France; Université Pierre & Marie Curie, Faculté de médecine Pitié Salpétrière, Paris, France; AP-HP, Hôpital de la Pitié-Salpétrière, Service de Neurologie Mazarin, Paris, France
4 Université Pierre & Marie Curie, Faculté de médecine Pitié Salpétrière, Paris, France; AP-HP, Hôpital de la Pitié-Salpétrière, Service de Neurologie Mazarin, Paris, France
5 INSERM, U711, Batiment de la nouvelle Pharmacie, 47 Bd de l’Hôpital, 75651 Paris cedex 13, France; Université Pierre & Marie Curie, Faculté de médecine Pitié Salpétrière, Paris, France
* To whom correspondence should be addressed. E-mail: everhard{at}ccr.jussieu.fr.
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Abstract |
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The O6-methylguanine-DNA methyltransferase gene (MGMT) is methylated in several cancers, including gliomas. However, the functional role of CpG island methylation in MGMT silencing is still controversial. The aim of this study was to investigate whether MGMT CpG island methylation correlates inversely with RNA expression of MGMT in glioblastomas and to determine the CpG region whose methylation best reflects the level of expression.
The methylation level of CpG sites that are potentially related to expression was investigated in 54 glioblastomas by pyrosequencing, a highly quantitative method, and analyzed with respect to their MGMT mRNA expression status. Three groups of patients were identified according to the methylation pattern of all 52 analyzed CpGs. Overall, an 85% rate of concordance was observed between methylation and expression (p<0.0001). When analyzing each CpG separately, six CpG sites were highly correlated with expression (p<0.0001) and two CpG regions could be used as surrogate markers for RNA expression in 81.5% of the patients.
This study indicates that there is a good statistical agreement between MGMT methylation and expression, and that some CpG regions better reflect MGMT expression than others. However, if transcriptional repression is the key mechanism in explaining the higher chemosensitivity of MGMT-methylated tumors, a substantial rate of discordance should lead clinicians to be cautious when deciding on a therapeutic strategy based on MGMT methylation status alone.
Key Words:
CpG island, expression, glioblastomas, methylation, MGMT
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