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Identification of Tumor-Specific Molecular Signatures in Intracranial Ependymoma and Association With Clinical Characteristics

Piergiorgio Modena, Elena Lualdi, Federica Facchinetti, Joris Veltman, James F. Reid, Simone Minardi, Irene Janssen, Felice Giangaspero, Marco Forni, Gaetano Finocchiaro, Lorenzo Genitori, Flavio Giordano, Riccardo Riccardi, Eric F.P.M. Schoenmakers, Maura Massimino, Gabriella Sozzi

From the Unit of Molecular Cytogenetics and Unit of Pediatric Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori; Fondazione Istituto FIRC di Oncologia Molecolare; Department of Experimental Neurosciences and Diagnostics, Istituto Neurologico C. Besta, Milano; Department of Experimental Medicine and Pathology, Università La Sapienza, Roma and Istituto Mediterraneo Neuromed, Pozzilli; Department of Pathology, Ospedale Infantile Regina Margherita, Torino; Division of Pediatric Neurosurgery, Ospedale Pediatrico Meyer, Firenze; Division of Paediatric Oncology, Catholic University, Rome, Italy; and Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Address reprint requests to Piergiorgio Modena, PhD, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, 20133 Milano, Italy; e-mail: piergiorgio.modena{at}istitutotumori.mi.it

Purpose To delineate clinically relevant molecular signatures of intracranial ependymoma.

Materials and Methods We analyzed 24 primary intracranial ependymomas. For genomic profiling, microarray-based comparative genomic hybridization (CGH) was used and results were validated by fluorescent in situ hybridization and loss of heterozygosity mapping. We performed gene expression profiling using microarrays, real-time quantitative reverse transcriptase polymerase chain reaction, and methylation analysis of selected genes. We applied class comparison analyses to compare both genomic and expression profiling data with clinical characteristics.

Results A variable number of genomic imbalances were detected by array CGH, revealing multiple regions of recurrent gain (including 2q23, 7p21, 12p, 13q21.1, and 20p12) and loss (including 5q31, 6q26, 7q36, 15q21.1, 16q24, 17p13.3, 19p13.2, and 22q13.3). An ependymoma-specific gene expression signature was characterized by the concurrent abnormal expression of developmental and differentiation pathways, including NOTCH and sonic hedgehog signaling. We identified specific differentially imbalanced genomic clones and gene expression signatures significantly associated with tumor location, patient age at disease onset, and retrospective risk for relapse. Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3).

Conclusion The present exploratory molecular profiling study allowed us to refine previously reported intervals of genomic imbalance, to identify novel restricted regions of gain and loss, and to identify molecular signatures correlating with various clinical variables. Validation of these results on independent data sets represents the next step before translation into the clinical setting.

Supported by Italian Association for Cancer Research (Inter-Regional Grant on Pediatric Oncology 2005-2007); Fondo per gli Investimenti della Ricerca di Base (Ministero dell'Istruzione, dell'Università e della Ricerca); Fondazione CARIPLO; The Nando Peretti Foundation; and Italian Ministry of Health (Ricerca Finalizzata).

E.F.P.M.S., M.M., and G.S. share senior co-authorship of this article.

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

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