title: Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas.
abstract: OBJECTIVE
  The molecular pathogenesis of pediatric ependymoma remains unclear. Our study was designed to identify genetic changes implicated in ependymoma progression.
  
  
  METHODS
  We characterized 59 ependymoma samples (33 at diagnosis and 26 at relapse) using array-comparative genomic hybridization (aCGH). Specific chromosomal imbalances were confirmed by fluorescent in situ hybridization, and candidate genes were assessed by real-time quantitative polymerase chain reaction (qPCR), immunohistochemistry, sequencing, and in vitro functional studies.
  
  
  RESULTS
  aCGH analysis revealed a significant increase in genomic imbalances on relapse compared with diagnosis, such as gain of 9qter and 1q (54% v 21% and 12% v 0%, respectively) and loss of 6q (27% v 6%). Supervised tumor classification showed that gain of 9qter was associated with tumor recurrence, age older than 3 years, and posterior fossa location. Using a candidate-gene strategy, we found an overexpression of two potential oncogenes at the locus 9qter: Tenascin-C and Notch1. Moreover, Notch pathway analysis (qPCR) revealed overexpression of Notch ligands, receptors, and target genes (Hes-1, Hey2, and c-Myc), and downregulation of Notch repressor Fbxw7. We confirmed by immunohistochemistry the overexpression of Tenascin-C and Hes-1. We detected Notch1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain). Furthermore, inhibition of Notch pathway with a gamma-secretase inhibitor impaired the growth of ependymoma stem cell cultures.
  
  
  CONCLUSIONS
  The activation of the Notch pathway and Tenascin-C seem to be important events in ependymoma progression and may represent future targets for therapy. We report, to our knowledge for the first time, recurrent oncogenic mutations in pediatric posterior fossa ependymomas.
authors.affiliation: Department of Neurosurgery, Peter B Dirks, Christian Sainte-Rose, and Gilles Vassal Hôpital Necker Enfants Malades, Université Paris Descartes, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Puget
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Carmela
authors.initials: C
authors.lastname: Dantas-Barbosa
authors.forename: Audrey
authors.initials: A
authors.lastname: Kauffmann
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.forename: Bastien
authors.initials: B
authors.lastname: Job
authors.forename: Clemens
authors.initials: C
authors.lastname: Dirven
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
authors.forename: Mathieu
authors.initials: M
authors.lastname: Peyre
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
authors.forename: Christian
authors.initials: C
authors.lastname: Sainte-Rose
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D018450:Disease Progression; D004806:Ependymoma / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D015192:Infratentorial Neoplasms / Q000235:genetics; D008297:Male; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D051880:Receptors, Notch / Q000235:genetics; D019063:Tenascin / Q000235:genetics; D055815:Young Adult
chemical_list: D051880:Receptors, Notch; D019063:Tenascin