Expression of O⁶-methylguanine-DNA methyltransferase in childhood medulloblastoma.
Medulloblastomas (MB) are the most common malignant brain tumors in childhood. Alkylator-based drugs are effective agents in the treatment of patients with MB. In several tumors, including malignant glioma, elevated O(6)-methylguanine-DNA methyltransferase (MGMT) expression levels or lack of MGMT promoter methylation have been found to be associated with resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ). In this study, we examined the MGMT status of MB and central nervous system primitive neuroectodermal tumor (PNET) cells and two large sets of primary MB. In seven MB/PNET cell lines investigated, MGMT promoter methylation was detected only in D425 human MB cells as assayed by the qualitative methylation-specific PCR and the more quantitative pyrosequencing assay. In D425 human MB cells, MGMT mRNA and protein expression was clearly lower when compared with the MGMT expression in the other MB/PNET cell lines. In MB/PNET cells, sensitivity towards TMZ and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) correlated with MGMT methylation and MGMT mRNA expression. Pyrosequencing in 67 primary MB samples revealed a mean percentage of MGMT methylation of 3.7-92% (mean: 13.25%, median: 10.67%). Percentage of MGMT methylation and MGMT mRNA expression as determined by quantitative RT-PCR correlated inversely (n = 46; Pearson correlation r (2) = 0.14, P = 0.01). We then analyzed MGMT mRNA expression in a second set of 47 formalin-fixed paraffin-embedded primary MB samples from clinically well-documented patients treated within the prospective randomized multicenter trial HIT'91. No association was found between MGMT mRNA expression and progression-free or overall survival. Therefore, it is not currently recommended to use MGMT mRNA expression analysis to determine who should receive alkylating agents and who should not.
Faoro
Denis
D
Neuro-Oncology Program, University Children's Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
von Bueren
André O
AO
Shalaby
Tarek
T
Sciuscio
Davide
D
Hürlimann
Marie-Louise
ML
Arnold
Lucia
L
Gerber
Nicolas U
NU
Haybaeck
Johannes
J
Mittelbronn
Michel
M
Rutkowski
Stefan
S
Hegi
Monika
M
Grotzer
Michael A
MA
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008130:Lomustine / Q000008:administration & dosage; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics*; D015337:Multicenter Studies as Topic; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000077204:Temozolomide
D012333:RNA, Messenger; D008130:Lomustine; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide
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