MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status.

Détails

Ressource 1Télécharger: BIB_BA1D07A69977.P001.pdf (696.30 [Ko])
Etat: Public
Version: de l'auteur⸱e
ID Serval
serval:BIB_BA1D07A69977
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status.
Périodique
Acta Neuropathologica
Auteur⸱e⸱s
Bady P., Sciuscio D., Diserens A.C., Bloch J., van den Bent M.J., Marosi C., Dietrich P.Y., Weller M., Mariani L., Heppner F.L., McDonald D.R., Lacombe D., Stupp R., Delorenzi M., Hegi M.E.
ISSN
1432-0533 (Electronic)
ISSN-L
0001-6322
Statut éditorial
Publié
Date de publication
2012
Peer-reviewed
Oui
Volume
124
Numéro
4
Pages
547-560
Langue
anglais
Notes
Publication types: Journal Article
Résumé
The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log-rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types.
Pubmed
Web of science
Open Access
Oui
Création de la notice
18/10/2012 17:07
Dernière modification de la notice
20/08/2019 15:28
Données d'usage