Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study.
O(6)-methylguanine-DNA methyltransferase (MGMT) is a repair enzyme that removes promutagenic O(6)-methylguanine adducts in DNA, to protect cells from acquisition of G:C--> A:T mutations. MGMT promoter methylation and polymorphisms may affect MGMT expression and activity. In the present study, we assessed MGMT promoter methylation and polymorphisms (Leu84Phe, Ile143Val, c.-56C>T) in 371 glioblastomas diagnosed at the population level. MGMT methylation was observed in 165 (44%) glioblastomas, with a higher frequency in females than males (53 vs. 39%; p = 0.0106) and in secondary than primary glioblastomas (73 vs. 43%; p = 0.0074). The frequency of TP53 G:C-->A:T mutations in glioblastomas with MGMT methylation was 25%, which was significantly higher than that in glioblastomas with MGMT methylation (16%; Fisher exact test; p = 0.0385). MGMT 143 Val allele in glioblastomas was significantly less frequent than in a healthy European Caucasian population, and was associated with longer survival than those with the MGMT 143 Ile allele (hazard ratio 0.70; 95% CI 0.48-1.01). These results suggest that MGMT methylation may be associated with susceptibility to acquire TP53 G:C-->A:T mutations, and that MGMT polymorphisms may affect the risk and prognosis of glioblastomas.
Zawlik
Izabela
I
International Agency for Research on Cancer, Lyon, France.
Vaccarella
Salvatore
S
Kita
Daisuke
D
Mittelbronn
Michel
M
Franceschi
Silvia
S
Ohgaki
Hiroko
H
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D020022:Genetic Predisposition to Disease; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019853:O(6)-Methylguanine-DNA Methyltransferase