MGMT gene silencing and benefit from temozolomide in glioblastoma.
BACKGROUND
Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.


METHODS
We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis.


RESULTS
The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups.


CONCLUSIONS
Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.
Hegi
Monika E
ME
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, University Hospital Lausanne, Lausanne, Switzerland. monika.hegi@chuv.hospvd.ch
Diserens
Annie-Claire
AC
Gorlia
Thierry
T
Hamou
Marie-France
MF
de Tribolet
Nicolas
N
Weller
Michael
M
Kros
Johan M
JM
Hainfellner
Johannes A
JA
Mason
Warren
W
Mariani
Luigi
L
Bromberg
Jacoline E C
JE
Hau
Peter
P
Mirimanoff
René O
RO
Cairncross
J Gregory
JG
Janzer
Robert C
RC
Stupp
Roger
R
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018572:Disease-Free Survival; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide