A 4-miRNA signature predicts the therapeutic outcome of glioblastoma.
Multimodal therapy of glioblastoma (GBM) reveals inter-individual variability in terms of treatment outcome. Here, we examined whether a miRNA signature can be defined for the a priori identification of patients with particularly poor prognosis.FFPE sections from 36 GBM patients along with overall survival follow-up were collected retrospectively and subjected to miRNA signature identification from microarray data. A risk score based on the expression of the signature miRNAs and cox-proportional hazard coefficients was calculated for each patient followed by validation in a matched GBM subset of TCGA. Genes potentially regulated by the signature miRNAs were identified by a correlation approach followed by pathway analysis.A prognostic 4-miRNA signature, independent of MGMT promoter methylation, age, and sex, was identified and a risk score was assigned to each patient that allowed defining two groups significantly differing in prognosis (p-value: 0.0001, median survival: 10.6 months and 15.1 months, hazard ratio = 3.8). The signature was technically validated by qRT-PCR and independently validated in an age- and sex-matched subset of standard-of-care treated patients of the TCGA GBM cohort (n=58). Pathway analysis suggested tumorigenesis-associated processes such as immune response, extracellular matrix organization, axon guidance, signalling by NGF, GPCR and Wnt. Here, we describe the identification and independent validation of a 4-miRNA signature that allows stratification of GBM patients into different prognostic groups in combination with one defined threshold and set of coefficients that could be utilized as diagnostic tool to identify GBM patients for improved and/or alternative treatment approaches.
Ludwig-Maximilians-University of Munich, Department of Radiation Oncology, Munich, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Maximilian
M
Niyazi
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.
Adriana
A
Pitea
Institute of Neurology (Edinger Institute), Goethe-University Frankfurt, Frankfurt/Main, Germany.
Michel
M
Mittelbronn
Dr. Senckenbergisches Institut für Neuroonkologie, Klinikum der J.W. Goethe-Universität, Frankfurt/Main, Germany.
Joachim
J
Steinbach
Zentrum für Medizinische Forschung, Medizinische Fakultät Mannheim, Mannheim, Germany.
Carsten
C
Sticht
Ludwig-Maximilians-University of Munich, Department of Radiation Oncology, Munich, Germany.|Department of Radiation Oncology, Paracelsus Medical University, Salzburg, Austria.
Franz
F
Zehentmayr
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.
Daniel
D
Piehlmaier
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.
Horst
H
Zitzelsberger
Ludwig-Maximilians-University of Munich, Department of Radiation Oncology, Munich, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.
Ute
U
Ganswindt
Department of Radiation Oncology, University Hospital, Frankfurt, Germany.
Claus
C
Rödel
Ludwig-Maximilians-University of Munich, Department of Radiation Oncology, Munich, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.
Kirsten
K
Lauber
Ludwig-Maximilians-University of Munich, Department of Radiation Oncology, Munich, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Claus
C
Belka
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany.|Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, Germany.
Kristian
K
Unger
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D059186:Chemoradiotherapy, Adjuvant; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000032:analysis*; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D059467:Transcriptome; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D035683:MicroRNAs
glioblastoma; miRNA; signature