Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents.
BACKGROUND
The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents.


METHODS
We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome.


RESULTS
The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status.


CONCLUSIONS
Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.
Esteller
M
M
Division of Cancer Biology, Johns Hopkins Oncology Center, Baltimore, MD 21231, USA.
Garcia-Foncillas
J
J
Andion
E
E
Goodman
S N
SN
Hidalgo
O F
OF
Vanaclocha
V
V
Baylin
S B
SB
Herman
J G
JG
D000704:Analysis of Variance; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002330:Carmustine / Q000494:pharmacology / Q000627:therapeutic use*; D018736:DNA Adducts; D019175:DNA Methylation; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D004351:Drug Resistance; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000502:physiology; D016019:Survival Analysis
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D004273:DNA, Neoplasm; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine