title: Prediction of clinical outcome in glioblastoma using a biologically relevant nine-microRNA signature.
abstract: BACKGROUND
  Glioblastoma is the most aggressive primary brain tumor, and is associated with a very poor prognosis. In this study we investigated the potential of microRNA expression profiles to predict survival in this challenging disease.
  
  
  METHODS
  MicroRNA and mRNA expression data from glioblastoma (n = 475) and grade II and III glioma (n = 178) were accessed from The Cancer Genome Atlas. LASSO regression models were used to identify a prognostic microRNA signature. Functionally relevant targets of microRNAs were determined using microRNA target prediction, experimental validation and correlation of microRNA and mRNA expression data.
  
  
  RESULTS
  A 9-microRNA prognostic signature was identified which stratified patients into risk groups strongly associated with survival (p = 2.26e-09), significant in all glioblastoma subtypes except the non-G-CIMP proneural group. The statistical significance of the microRNA signature was higher than MGMT methylation in temozolomide treated tumors. The 9-microRNA risk score was validated in an independent dataset (p = 4.50e-02) and also stratified patients into high- and low-risk groups in lower grade glioma (p = 5.20e-03). The majority of the 9 microRNAs have been previously linked to glioblastoma biology or treatment response. Integration of the expression patterns of predicted microRNA targets revealed a number of relevant microRNA/target pairs, which were validated in cell lines.
  
  
  CONCLUSIONS
  We have identified a novel, biologically relevant microRNA signature that stratifies high- and low-risk patients in glioblastoma. MicroRNA/mRNA interactions identified within the signature point to novel regulatory networks. This is the first study to formulate a survival risk score for glioblastoma which consists of microRNAs associated with glioblastoma biology and/or treatment response, indicating a functionally relevant signature.
authors.affiliation: Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Josie
authors.initials: J
authors.lastname: Hayes
authors.affiliation: Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Helene
authors.initials: H
authors.lastname: Thygesen
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire PR1 2HE, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Tumilson
authors.affiliation: Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Droop
authors.affiliation: Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Boissinot
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hughes
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Westhead
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire PR1 2HE, UK.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Alder
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire PR1 2HE, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Shaw
authors.affiliation: Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Short
authors.affiliation: Harvey Cushing Neurooncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: slawler@partners.org.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
mesh_terms: D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D012044:Regression Analysis; D012307:Risk Factors; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D035683:MicroRNAs; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Glioblastoma; MicroRNA; Prognosis; Signature; TCGA