Expression of O⁶-methylguanine-DNA methyltransferase in childhood medulloblastoma.

Détails

ID Serval
serval:BIB_BE7686BEC2CD
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Expression of O⁶-methylguanine-DNA methyltransferase in childhood medulloblastoma.
Périodique
Journal of Neuro-oncology
Auteur(s)
Faoro D., von Bueren A.O., Shalaby T., Sciuscio D., Hürlimann M.L., Arnold L., Gerber N.U., Haybaeck J., Mittelbronn M., Rutkowski S., Hegi M., Grotzer M.A.
ISSN
1573-7373 (Electronic)
ISSN-L
0167-594X
Statut éditorial
Publié
Date de publication
2011
Peer-reviewed
Oui
Volume
103
Numéro
1
Pages
59-69
Langue
anglais
Résumé
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.
Mots-clé
Adolescent, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Blotting, Western, Cell Proliferation/drug effects, Cerebellar Neoplasms/drug therapy, Cerebellar Neoplasms/genetics, Child, Child, Preschool, DNA Methylation, Dacarbazine/administration & dosage, Dacarbazine/analogs & derivatives, Female, Gene Expression Regulation, Enzymologic/physiology, Humans, Immunoenzyme Techniques, Lomustine/administration & dosage, Male, Medulloblastoma/drug therapy, Medulloblastoma/genetics, Multicenter Studies as Topic, Neuroectodermal Tumors, Primitive/drug therapy, Neuroectodermal Tumors, Primitive/genetics, O(6)-Methylguanine-DNA Methyltransferase/genetics, Prognosis, Promoter Regions, Genetic/genetics, Prospective Studies, RNA, Messenger/genetics, Randomized Controlled Trials as Topic, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate
Pubmed
Web of science
Création de la notice
05/10/2010 21:28
Dernière modification de la notice
20/08/2019 16:32
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