title: Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact.
abstract: Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21-Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with Class B tumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21-Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21-Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes.
  
  
  CONCLUSIONS
  Molecular profiling-based classification of glioblastoma (GBM) into four subtypes has substantially increased our understanding of the biology of the disease and has pointed to the heterogeneous nature of GBM. However, this classification is not mechanism based and its prognostic value is limited. Here, we identify a new mechanism in GBM (the miR-21-Sox2 axis) that can classify ∼50% of patients into two subtypes with distinct molecular, radiological, and pathological characteristics. Importantly, this classification can predict patient survival better than the currently used parameters. Further, analysis of the miR-21-Sox2 relationship in mouse neural stem cells and in the mouse brain at different developmental stages indicates that miR-21 and Sox2 are predominantly expressed in mutually exclusive patterns, suggesting a role in normal neural development.
authors.affiliation: Departments of Genetics, Department of Clinical Neurosciences, University Hospital (CHUV BH19-110), Lausanne 1011, Switzerland, and.
authors.forename: Pratheesh
authors.initials: P
authors.lastname: Sathyan
authors.affiliation: Departments of Genetics.
authors.forename: Pascal O
authors.initials: PO
authors.lastname: Zinn
authors.affiliation: Departments of Genetics.
authors.forename: Anantha L
authors.initials: AL
authors.lastname: Marisetty
authors.affiliation: Departments of Genetics.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Departments of Genetics.
authors.forename: Mohamed Mostafa
authors.initials: MM
authors.lastname: Kamal
authors.affiliation: Departments of Genetics.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Department of Clinical Neurosciences, University Hospital (CHUV BH19-110), Lausanne 1011, Switzerland, and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bady
authors.affiliation: Departments of Genetics.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.affiliation: Pathology.
authors.forename: Khalida M
authors.initials: KM
authors.lastname: Wani
authors.affiliation: Departments of Genetics.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Veo
authors.affiliation: Neurosurgery.
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.affiliation: Departments of Genetics.
authors.forename: Dina Hamada
authors.initials: DH
authors.lastname: Kassem
authors.affiliation: Departments of Genetics.
authors.forename: Frederick
authors.initials: F
authors.lastname: Robinson
authors.affiliation: Departments of Genetics.
authors.forename: Connie
authors.initials: C
authors.lastname: Weng
authors.affiliation: Biostatistics.
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.affiliation: Neurosurgery, The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Dima
authors.initials: D
authors.lastname: Suki
authors.affiliation: Neuro-Oncology.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.affiliation: Translational Molecular Pathology.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Bhat
authors.affiliation: Neurosurgery, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Pathology, Bioinformatics, and.
authors.forename: Ken
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Diagnostic Radiology, and.
authors.forename: Rivka R
authors.initials: RR
authors.lastname: Colen
authors.affiliation: Bioinformatics, and The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
authors.affiliation: Neuro-Oncology, The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Pathology, The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.affiliation: Neurosurgery, The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.affiliation: Neurosurgery, The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.affiliation: Neurosurgery, The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Raymond
authors.initials: R
authors.lastname: Sawaya
authors.affiliation: Department of Clinical Neurosciences, University Hospital (CHUV BH19-110), Lausanne 1011, Switzerland, and.
authors.forename: Monika
authors.identifier: http://orcid.org/0000-0003-0855-6495
authors.initials: M
authors.lastname: Hegi
authors.affiliation: Departments of Genetics, Neuro-Oncology, The Brain Tumor Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030 smajumder@mdanderson.org.
authors.forename: Sadhan
authors.initials: S
authors.lastname: Majumder
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000145:classification* / Q000175:diagnosis / Q000378:metabolism*; D002478:Cells, Cultured; D005909:Glioblastoma / Q000145:classification* / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis*; D011379:Prognosis; D012189:Retrospective Studies; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis*; D015996:Survival Rate / Q000639:trends
chemical_list: D014408:Biomarkers, Tumor; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
keywords: SOX2; glioblastoma; microRNA-21; neuronal subtype