Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres.

Détails

ID Serval
serval:BIB_8D444B905B51
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres.
Périodique
Clinical Cancer Research
Auteur(s)
Sciuscio D., Diserens A.C., van Dommelen K., Martinet D., Jones G., Janzer R.C., Pollo C., Hamou M.F., Kaina B., Stupp R., Levivier M., Hegi M.E.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Statut éditorial
Publié
Date de publication
2011
Volume
17
Numéro
2
Pages
255-266
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Résumé
Purpose: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma.
Experimental Design: Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity.
Results: In glioblastoma, MGMT-methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception (<50%). The CpG methylation patterns were characteristic for each glioblastoma exhibiting 25% to 90% methylated CpGs of 28 sites interrogated. Furthermore, MGMT promoter methylation was associated with a nonpermissive chromatin status in accordance with very low MGMT transcript levels and undetectable MGMT activity.
Conclusions: In MGMT-methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy. Clin Cancer Res; 17(2); 255-66. (C)2010 AACR.
Pubmed
Web of science
Création de la notice
22/02/2011 12:57
Dernière modification de la notice
03/03/2018 19:15
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