CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas.
OBJECTIVE
The DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents, and its loss in cancer cells is associated with hypermethylation of the MGMT CpG island. Thus, methylation of MGMT has been correlated with the clinical response to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in primary gliomas. Here, we investigate whether the presence of MGMT methylation in gliomas is also a good predictor of response to another emergent alkylating agent, temozolomide.


METHODS
Using a methylation-specific PCR approach, we assessed the methylation status of the CpG island of MGMT in 92 glioma patients who received temozolomide as first-line chemotherapy or as treatment for relapses.


RESULTS
Methylation of the MGMT promoter positively correlated with the clinical response in the glioma patients receiving temozolomide as first-line chemotherapy (n = 40). Eight of 12 patients with MGMT-methylated tumors (66.7%) had a partial or complete response, compared with 7 of 28 patients with unmethylated tumors (25.0%; P = 0.030). We also found a positive association between MGMT methylation and clinical response in those patients receiving BCNU (n = 35, P = 0.041) or procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (n = 17, P = 0.043) as first-line chemotherapy. Overall, if we analyze the clinical response of all of the first-line chemotherapy treatments with temozolomide, BCNU, and procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea as a group in relation to the MGMT methylation status, MGMT hypermethylation was strongly associated with the presence of partial or complete clinical response (P < 0.001). Finally, the MGMT methylation status determined in the initial glioma tumor did not correlate with the clinical response to temozolomide when this drug was administered as treatment for relapses (P = 0.729).


CONCLUSIONS
MGMT methylation predicts the clinical response of primary gliomas to first-line chemotherapy with the alkylating agent temozolomide. These results may open up possibilities for more customized treatments of human brain tumors.
Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Madrid, Spain.
Maria F
MF
Paz
Ricard
R
Yaya-Tur
Iñigo
I
Rojas-Marcos
Gaspar
G
Reynes
Marina
M
Pollan
Lucinda
L
Aguirre-Cruz
Jose Luis
JL
García-Lopez
Jose
J
Piquer
María-Jose
MJ
Safont
Carmen
C
Balaña
Montserrat
M
Sanchez-Cespedes
Mercedes
M
García-Villanueva
Leoncio
L
Arribas
Manel
M
Esteller
D000328:Adult; D000368:Aged; D000477:Alkylating Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy; D002330:Carmustine / Q000494:pharmacology; D018899:CpG Islands; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005910:Glioma / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D016896:Treatment Outcome
D000477:Alkylating Agents; D003606:Dacarbazine; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine; D000077204:Temozolomide