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Molecular Profiling Identifies Prognostic Subgroups of Pediatric Glioblastoma and Shows Increased YB-1 Expression in Tumors

Damien Faury, André Nantel, Sandra E. Dunn, Marie-Christine Guiot, Takrima Haque, Péter Hauser, Miklós Garami, László Bognár, Zoltán Hanzély, Pawel P. Liberski, Enrique Lopez-Aguilar, Elvis T. Valera, Luis G. Tone, Anne-Sophie Carret, Rolando F. Del Maestro, Martin Gleave, Jose-Luis Montes, Torsten Pietsch, Stephen Albrecht, Nada Jabado

From the Division of Hemato-Oncology, Department of Pediatrics; Department of Pathology, Montréal Children's Hospital Research Institute; Division of Neuro-Surgery, Montréal Children's Hospital; Division of Neuro-Surgery and the Brain Tumor Research Center, Montréal Neurological Institute, McGill University Health Center; Biotechnology Research Institute, National Research Council of Canada, Montréal; Laboratory for Oncogenomic Research, Department of Pediatrics, British Columbia Research Institute for Children's and Women's Health; Department of Surgery, Prostate Cancer Center, Jack Bell Research Laboratories, Vancouver; Second Department of Pediatrics, Semmelweis University; Division of Neuro-surgery, Division of Pathology, National Institute of Neurosurgery, Budapest, Hungary; Department of Neuropathology, Medical University of Lodz, Lodz, Poland; Oncology Department, Pediatrics Hospital, Centro Medico Nacional Siglo XXI, Mexico City, Mexico; Department of Pediatrics, University Hospital, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil; Institut of Neuropathology, University of Bonn, Bonn, Germany

Address reprint requests to Nada Jabado, MD, PhD, Montreal Children's Hospital Research Institute, 4060 Ste Catherine West, PT-239, Montreal, Quebec, Canada H3Z 2Z3; e-mail: nada.jabado{at}mcgill.ca

Purpose: Pediatric glioblastoma (pGBM) is a rare, but devastating brain tumor. In contrast to GBM in adults (aGBM), little is known about the mechanisms underlying its development. Our aim is to gain insight into the molecular pathways of pGBM.

Materials and Methods: Thirty-two pGBM and seven aGBM samples were investigated using biochemical and transcriptional profiling. Ras and Akt pathway activation was assessed through the phosphorylation of downstream effectors, and gene expression profiles were generated using the University Health Network Human 19K cDNA arrays. Results were validated using real-time polymerase chain reaction and immunohistochemistry and compared with existing data sets on aGBM.

Results: There are at least two subsets of pGBM. One subset, associated with Ras and Akt pathway activation, has very poor prognosis and exhibits increased expression of genes related to proliferation and to a neural stem-cell phenotype, similar to findings in aggressive aGBM. This subset was still molecularly distinguishable from aGBM after unsupervised and supervised analysis of expression profiles. A second subset, with better prognosis, is not associated with activation of Akt and Ras pathways, may originate from astroglial progenitors, and does not express gene signatures and markers shown to be associated with long-term survival in aGBM. Both subsets of pGBM show overexpression of Y-box-protein-1 that may help drive oncogenesis in this tumor.

Conclusion: Our work, the first study of gene expression profiles in pGBM, provides valuable insight into active pathways and targets in a cancer with minimal survival, and suggests that these tumors cannot be understood exclusively through studies of aGBM.

Supported by the Canadian Institute of Health Research and the Penny Cole Foundation (N.J.), an NRC Genome Health Initiative grant (A.N.), the Hungarian Scientific Research Fund (O.T.K.A.) Contract No. T-04639, and the National Research and Development Fund (N.K.F.P.) Contract No. 1A/002/2004 (P.H., M.G., L.B., Z.H.). N.J. is the recipient of a Chercheur Boursier Award from Fonds de la Recherche en Sante du Québec.

D.F. and A.N. contributed equally to this article.

This is National Research Council publication No. 47482.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

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