Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial.

Abstract

BACKGROUND:

Molecular biomarkers including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, and O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation may improve prognostication and guide treatment decisions for patients with World Health Organization (WHO) anaplastic gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) enable the determination of large-scale methylation profiles and genome-wide DNA copy number changes. Algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion, and MGMT promoter methylation using a single assay.

METHODS:

Here, we retrospectively investigated the diagnostic and prognostic performance of these algorithms in comparison to individual marker testing and patient outcome in the biomarker cohort (n = 115 patients) of the NOA-04 trial.

RESULTS:

Concordance for IDH and 1p/19q status was very high: In 92% of samples, the HM450 and reference data agreed. In discordant samples, survival analysis by Kaplan-Meier and Cox regression analyses suggested a more accurate assessment of biological phenotype by the HM450 analysis. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of samples than conventional methylation-specific PCR, with 87 of 91 G-CIMP tumors predicted as MGMT promoter-methylated. Pyrosequencing of discordant samples confirmed the HM450 assessment in 14 of 17 cases.

CONCLUSIONS:

G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and are associated with prognosis in the NOA-04 trial. For MGMT, HM450 suggests promoter methylation in the vast majority of G-CIMP tumors, which is supported by pyrosequencing.

• Authors: Benedikt Wiestler, David Capper, Volker Hovestadt, Martin Sill, David T W Jones, Christian Hartmann, Joerg Felsberg, Michael Platten, Wolfgang Feiden, Kathy Keyvani, Stefan M Pfister, Otmar D Wiestler, Richard Meyermann, Guido Reifenberger, Thorsten Pietsch, Andreas von Deimling, Michael Weller, Wolfgang Wick
• Journal: Neuro-oncology (Neuro Oncol) Vol. 16 Issue 12 Pg. 1630-8 (Dec 2014) ISSN: 1523-5866 [Electronic] England
• PMID: 25028501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Biomarkers
• Tumor Suppressor Proteins
• Isocitrate Dehydrogenase
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes

Topics

• Adult
• Aged
• Algorithms
• Biomarkers
• Brain Neoplasms (diagnosis, genetics)
• Chromosomes, Human, Pair 1 (genetics)
• Chromosomes, Human, Pair 19 (genetics)
• CpG Islands
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Female
• Gene Deletion
• Glioma (diagnosis, genetics)
• Humans
• Isocitrate Dehydrogenase (genetics)
• Male
• Middle Aged
• Phenotype
• Promoter Regions, Genetic
• Retrospective Studies
• Tumor Suppressor Proteins (genetics)
• Young Adult