TY - JOUR
T1 - Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas
AU - Everhard, Sibille
AU - Tost, Jörg
AU - El Abdalaoui, Hafida
AU - Crinière, Emmanuelle
AU - Busato, Florence
AU - Marie, Yannick
AU - Gut, Ivo G.
AU - Sanson, Marc
AU - Mokhtari, Karima
AU - Laigle-Donadey, Florence
AU - Hoang-Xuan, Khê
AU - Delattre, Jean Yves
AU - Thillet, Joëlle
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
KW - CpG island methylation
KW - Expression
KW - Glioblastomas
KW - MGMT
UR - http://www.scopus.com/inward/record.url?scp=68949149010&partnerID=8YFLogxK
U2 - 10.1215/15228517-2009-001
DO - 10.1215/15228517-2009-001
M3 - Article
C2 - 19224763
AN - SCOPUS:68949149010
SN - 1522-8517
VL - 11
SP - 348
EP - 356
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 4
ER -
