title: Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma.
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.
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wiestler
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Martin
authors.initials: M
authors.lastname: Sill
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.forename: Christian
authors.initials: C
authors.lastname: Koelsche
authors.forename: Anna
authors.initials: A
authors.lastname: Bertoni
authors.forename: Leonille
authors.initials: L
authors.lastname: Schweizer
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Elisa K
authors.initials: EK
authors.lastname: Weiß
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Schliesser
authors.forename: Alexander
authors.initials: A
authors.lastname: Radbruch
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics*; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D005858:Germany; D005910:Glioma / Q000145:classification* / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein; D045643:DNA Repair Enzymes