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

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

doi:10.1093/neuonc/nou138

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

Neuro Oncol. 2014 Dec;16(12):1630-8. doi: 10.1093/neuonc/nou138. Epub 2014 Jul 15.

Authors

Benedikt Wiestler¹, David Capper¹, Volker Hovestadt¹, Martin Sill¹, David T W Jones¹, Christian Hartmann¹, Joerg Felsberg¹, Michael Platten¹, Wolfgang Feiden¹, Kathy Keyvani¹, Stefan M Pfister¹, Otmar D Wiestler¹, Richard Meyermann¹, Guido Reifenberger¹, Thorsten Pietsch¹, Andreas von Deimling¹, Michael Weller¹, Wolfgang Wick¹

Affiliation

¹ Department of Neurooncology (B.W., M.P., W.W.); Department of Neuropathology (D.C., A.v.D.); Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital (S.M.P.); Clinical Cooperation Units Neurooncology (B.W., W.W.), Neuropathology (D.C, A.v.D.); Neuroimmunology and Brain Tumor Immunology (M.P.); Division of Molecular Genetics (V.H.); Division of Biostatistics (M.S.); Division of Pediatric Neurooncology (S.M.P., D.T.W.J.), German Cancer Research Center (DKFZ), Heidelberg, Germany (O.D.W.) and German Cancer Consortium (DKTK); Department for Neuropathology, Institute of Pathology, Medical University of Hannover, Hannover, Germany (C.H.); Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany (J.F., G.R.); German Consortium for Translational Cancer Research (DKTK), Düsseldorf, Germany (M.P., G.R.); Institute for Neuropathology, Saarland University, 66421 Saarbrücken, Germany (W.F.); Institute for Neuropathology, University of Essen Medical School, Essen, Germany (K.K.); Institute for Neuropathology, University of Tübingen, Tübingen, Germany (R.M.); Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany (T.P.); Department of Neurology, University Hospital Zurich, Zürich, Switzerland (M.W.).

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.

Keywords: 1p/19q; 450k; G-CIMP; MGMT; anaplastic glioma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Algorithms
Biomarkers
Brain Neoplasms / diagnosis*
Brain Neoplasms / 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*
Glioma / genetics*
Humans
Isocitrate Dehydrogenase / genetics
Male
Middle Aged
Phenotype
Promoter Regions, Genetic
Retrospective Studies
Tumor Suppressor Proteins / genetics
Young Adult

Substances

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