title: Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.
abstract: OBJECTIVE
  Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.
  
  
  METHODS
  We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets.
  
  
  RESULTS
  Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals.
  
  
  CONCLUSIONS
  Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
authors.affiliation: Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Aviad
authors.initials: A
authors.lastname: Tsherniak
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.forename: Azra
authors.initials: A
authors.lastname: Ligon
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Rameen
authors.initials: R
authors.lastname: Berhoukim
authors.forename: Vladimir
authors.initials: V
authors.lastname: Amani
authors.forename: Liliana
authors.initials: L
authors.lastname: Goumnerova
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Keith
authors.initials: K
authors.lastname: Ligon
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
mesh_terms: D000465:Algorithms; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C116115:MYCBP protein, human; D012334:RNA, Neoplasm; D014157:Transcription Factors