Originally published as JCO Early Release 10.1200/JCO.2007.15.4195 on March 16 2009

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Candidate Genes on Chromosome 9q33-34 Involved in the Progression of Childhood Ependymomas

From the Department of Neurosurgery, Hôpital Necker Enfants Malades, Université Paris Descartes; Department of Pediatric Oncology; Centre National de la Recherche Scientifique – Formation de Recherche en Evolution 2939; Unité Propre de Recherche de I'Enseignement Supérieur Equipe d'Accueil 3535; Laboratory of Translational Research, Institut Gustave Roussy, Villejuif; INSERM (L'Institut National de la Santé et de la Recherche Médicale) U745; Department of Pathology, Hôpital Sainte-Anne, Université Paris Descartes, Paris, France; Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, the Netherlands; and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

Corresponding author: Jacques Grill, MD, PhD, Department of Pediatric and Adolescent Oncology, Institut Gustave Roussy, Villejuif, France; e-mail: grill{at}igr.fr.

Purpose The molecular pathogenesis of pediatric ependymoma remains unclear. Our study was designed to identify genetic changes implicated in ependymoma progression.

Patients and 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 -secretase inhibitor impaired the growth of ependymoma stem cell cultures.

Conclusion 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.

Supported in part by National Institute of Cancer Grant No. PL-046 (J.G.); Association pour la Recherche en Neurochirurgie Pédiatrique, "L'Etoile de Martin" (C.D.B.); Mr O. Misoff and Les Entreprises du Médicament Recherche (S.P.); and "Rayon Vert" (G.V.).

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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