title: Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.
abstract: Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.
authors.affiliation: Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland, michael.weller@usz.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
authors.forename: Edith
authors.initials: E
authors.lastname: Willscher
authors.forename: Vera
authors.initials: V
authors.lastname: Riehmer
authors.forename: Bettina
authors.initials: B
authors.lastname: Hentschel
authors.forename: Markus
authors.initials: M
authors.lastname: Kreuz
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Ulrike
authors.initials: U
authors.lastname: Beyer
authors.forename: Henry
authors.initials: H
authors.lastname: Löffler-Wirth
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kaulich
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Dorothee
authors.initials: D
authors.lastname: Gramatzki
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.forename: Tobias
authors.initials: T
authors.lastname: Martens
authors.forename: Jan
authors.initials: J
authors.lastname: Boström
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.forename: Michael
authors.initials: M
authors.lastname: Sabel
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Tonn
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Susan
authors.initials: S
authors.lastname: Noell
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Hans
authors.initials: H
authors.lastname: Binder
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D023281:Genomics / Q000379:methods*; D005910:Glioma / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading / Q000379:methods; D011379:Prognosis; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D014944:World Health Organization; D055815:Young Adult
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human