title: Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling.
abstract: The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
authors.forename: Vera
authors.initials: V
authors.lastname: Riehmer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kaulich
authors.forename: Edith
authors.initials: E
authors.lastname: Willscher
authors.forename: Henry
authors.initials: H
authors.lastname: Wirth
authors.forename: Jens
authors.initials: J
authors.lastname: Gietzelt
authors.forename: Bettina
authors.initials: B
authors.lastname: Hentschel
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.forename: Jakob
authors.initials: J
authors.lastname: Matschke
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sabel
authors.forename: Dorothee
authors.initials: D
authors.lastname: Gramatzki
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Tonn
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Hans
authors.initials: H
authors.lastname: Binder
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D017741:Survivors; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D025521:Tumor Suppressor Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: IDH1; MGMT; array-based comparative genomic hybridization; gene expression profiles; glioblastoma; integrative bioinformatics; long-term survival