title: Medulloblastoma comprises four distinct molecular variants.
abstract: OBJECTIVE
  Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups.
  
  
  METHODS
  We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays.
  
  
  RESULTS
  Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status.
  
  
  CONCLUSIONS
  Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Stephen
authors.initials: S
authors.lastname: Mack
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Hawkins
authors.forename: Pim
authors.initials: P
authors.lastname: French
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000704:Analysis of Variance; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D002648:Child; D004252:DNA Mutational Analysis; D018450:Disease Progression; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D051662:Kv1.1 Potassium Channel / Q000235:genetics*; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D025341:Principal Component Analysis; D011379:Prognosis; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D015398:Signal Transduction; D012984:Software; D015996:Survival Rate; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051662:Kv1.1 Potassium Channel; D008565:Membrane Proteins; D017461:Receptors, Atrial Natriuretic Factor; D051176:beta Catenin; C501126:DKK1 protein, human; C496946:KCNA1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C073616:atrial natriuretic factor receptor C
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