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

摘要: 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 anaplastic glioma suggest a prognostic value MGMT methylation. Investigation pathogenetic and epigenetic features this intriguingly distinct behavior requires accurate classification to assess high throughput molecular databases. Promoter methylation-mediated silencing strongly dependent on location methylated CpGs, complicating classification. Using HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated gene, with 14 located promoter, two regions CpG island promoter were identified importance outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg12434587 [corrected] cg12981137 provided good properties (kappa = 0.85; log-rank p < 0.001) using training-set 63 glioblastomas homogenously treated patients, whom was previously shown be based by methylation-specific PCR. MGMT-STP27 successfully validated independent cohort chemo-radiotherapy-treated glioblastoma patients (n 50; kappa 0.88; outcome, 0.001). Lower prevalence among methylator phenotype (CIMP) positive tumors found Cancer Genome Atlas than low grade cohorts, while CIMP-negative gliomas classified as approximately 50 % regardless tumor grade. proposed prediction allows mining datasets derived HM-450K or HM-27K explore effects context suspected modulate treatment resistance different types.