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. 2014 Oct;128(4):561-71.
doi: 10.1007/s00401-014-1315-x. Epub 2014 Jul 10.

Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma

Benedikt Wiestler  1 , David Capper, Martin Sill, David T W Jones, Volker Hovestadt, Dominik Sturm, Christian Koelsche, Anna Bertoni, Leonille Schweizer, Andrey Korshunov, Elisa K Weiß, Maximilian G Schliesser, Alexander Radbruch, Christel Herold-Mende, Patrick Roth, Andreas Unterberg, Christian Hartmann, Torsten Pietsch, Guido Reifenberger, Peter Lichter, Bernhard Radlwimmer, Michael Platten, Stefan M Pfister, Andreas von Deimling, Michael Weller, Wolfgang Wick
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Free article

Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma

Benedikt Wiestler et al. Acta Neuropathol. 2014 Oct.
Free article

Abstract

The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMP(pos) (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMP(neg) (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMP(neg) glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMP(pos) tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMP(pos) tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMP(neg) anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.

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