1. 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 (vol 124, pg 547, 2012)
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Luigi Mariani, Jocelyne Bloch, Christine Marosi, Mauro Delorenzi, Denis Lacombe, Roger Stupp, Pierre-Yves Dietrich, Monika E. Hegi, Pierre Bady, Annie Claire Diserens, Martin J. van den Bent, Michael Weller, David R. Mcdonald, Davide Sciuscio, Frank L. Heppner, Neurology, University of Zurich, and Hegi, M E
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Methyltransferase ,2804 Cellular and Molecular Neuroscience ,Brain Neoplasms/classification/genetics ,Bioinformatics ,Infinium methylation platform ,0302 clinical medicine ,Data Mining ,Promoter Regions, Genetic ,DNA Modification Methylases ,Oligonucleotide Array Sequence Analysis ,ddc:616 ,0303 health sciences ,DNA methylation ,Brain Neoplasms ,Methylation ,DNA Repair Enzymes/genetics ,Prognosis ,3. Good health ,2728 Neurology (clinical) ,Phenotype ,CpG site ,030220 oncology & carcinogenesis ,DNA Modification Methylases/genetics ,MGMT ,DNA Methylation/genetics ,Clinical Neurology ,610 Medicine & health ,Biology ,Tumor Suppressor Proteins/genetics ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,SDG 3 - Good Health and Well-being ,Prediction model ,Gene silencing ,Humans ,Epigenetics ,Gene Silencing ,Gene ,neoplasms ,030304 developmental biology ,Original Paper ,Models, Statistical ,CpG Island Methylator Phenotype ,Tumor Suppressor Proteins ,MSP ,Promoter Regions, Genetic/genetics ,digestive system diseases ,10040 Clinic for Neurology ,High-Throughput Screening Assays ,2734 Pathology and Forensic Medicine ,Glioblastoma/classification/genetics ,DNA Repair Enzymes ,Logistic Models ,Cancer research ,CpG Islands ,Neurology (clinical) ,Neoplasm Grading ,Glioblastoma - Abstract
The methylation status of the O6-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