Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling

TY - JOUR

T1 - Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling

AU - Reifenberger, Guido

AU - Weber, Ruthild G

AU - Riehmer, Vera

AU - Kaulich, Kerstin

AU - Willscher, Edith

AU - Wirth, Henry

AU - Gietzelt, Jens

AU - Hentschel, Bettina

AU - Westphal, Manfred

AU - Simon, Matthias

AU - Schackert, Gabriele

AU - Schramm, Johannes

AU - Matschke, Jakob

AU - Sabel, Michael C

AU - Gramatzki, Dorothee

AU - Felsberg, Jörg

AU - Hartmann, Christian

AU - Steinbach, Joachim P

AU - Schlegel, Uwe

AU - Wick, Wolfgang

AU - Radlwimmer, Bernhard

AU - Pietsch, Torsten

AU - Tonn, Jörg C

AU - von Deimling, Andreas

AU - Binder, Hans

AU - Weller, Michael

AU - Loeffler, Markus

AU - German Glioma Network

N1 - © 2014 UICC.

PY - 2014/10/15

Y1 - 2014/10/15

N2 - 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.

AB - 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.

KW - Brain Neoplasms

KW - DNA Modification Methylases

KW - DNA Repair Enzymes

KW - Gene Dosage

KW - Gene Expression Profiling

KW - Genome, Human

KW - Glioblastoma

KW - Humans

KW - Isocitrate Dehydrogenase

KW - Mutation

KW - Oligonucleotide Array Sequence Analysis

KW - Promoter Regions, Genetic

KW - Prospective Studies

KW - Survivors

KW - Transcriptome

KW - Tumor Suppressor Proteins

U2 - 10.1002/ijc.28836

DO - 10.1002/ijc.28836

M3 - SCORING: Journal article

C2 - 24615357

VL - 135

SP - 1822

EP - 1831

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 8

ER -