title: Molecular subtypes of glioblastoma are relevant to lower grade glioma.
abstract: BACKGROUND
  Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas).
  
  
  METHODS
  Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al.
  
  
  RESULTS
  Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.
  
  
  CONCLUSIONS
  GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Guan
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Internal Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Jaime
authors.initials: J
authors.lastname: Vengoechea
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Neurological Surgery, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Brian Patrick
authors.initials: BP
authors.lastname: O'Neill
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: de Groot
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Yust-Katz
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Wai-Kwan Alfred
authors.initials: WK
authors.lastname: Yung
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Rosenfeld
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Roeland G W
authors.initials: RG
authors.lastname: Verhaak
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
mesh_terms: D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D005910:Glioma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D016019:Survival Analysis
chemical_list: D007521:Isocitrate Dehydrogenase