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Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas

French National Institute for Health and Medical Research (INSERM), Paris (S.E., E.C., Y.M., M.S., F.L.-D., K.H.-X., J.-Y.D., J.T.); Université Pierre and Marie Curie, Faculté de Médecine, Hôpital de la Pitié-Salpétrière, Paris (S.E., E.C., Y.M., M.S., K.M., F.L.-D., K.H.-X., J.-Y.D., J.T.); Laboratory for Epigenetics, Centre National de Génotypage, Commissariat à l'Énergie Atomique, Institut de Génomique, Evry (J.T., H.E.A., F.B., I.G.G.); Assistance Publique–Hôpitaux de Paris, Hôpital de la Pitié-Salpétrière, Service de Neurologie Mazarin, Paris (M.S., K.M., F.L.-D., K.H.-X., J.-Y.D.); France

Address correspondence to Sibille Everhard, INSERM, U711, Batiment de la nouvelle Pharmacie, 47 Bd de l'Hôpital, 75651 Paris cedex 13, France (everhard{at}ccr.jussieu.fr).

The O⁶-methylguanine-DNA methyltransferase gene (MGMT) is methylated in several cancers, including gliomas. However, the functional role of cysteine-phosphate-guanine (CpG) island (CGI) methylation in MGMT silencing is still controversial. The aim of this study was to investigate whether MGMT CGI 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 CpG sites. 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 good statistical agreement between MGMT methylation and expression, and that some CpG regions better reflect MGMT expression than do 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 methylation • expression • glioblastomas • MGMT

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