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

Sibille Everhard*, Jörg Tost, Hafida El Abdalaoui, Emmanuelle Crinière, Florence Busato, Yannick Marie, Ivo G. Gut, Marc Sanson, Karima Mokhtari, Florence Laigle-Donadey, Khê Hoang-Xuan, Jean Yves Delattre, Joëlle Thillet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

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 methyl ation 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.

Original languageEnglish (US)
Pages (from-to)348-356
Number of pages9
JournalNeuro-Oncology
Volume11
Issue number4
DOIs
StatePublished - Aug 1 2009

Keywords

  • CpG island methylation
  • Expression
  • Glioblastomas
  • MGMT

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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