A prognostic gene expression signature in infratentorial ependymoma
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Patients with ependymoma exhibit a wide range of clinical outcomes that are currently unexplained by clinical or histological factors. Little is known regarding molecular biomarkers that could predict clinical behavior. Since recent data suggest that these tumors display biological characteristics according to their location (cerebral vs. infratentorial vs. spinal cord), rather than explore a broad spectrum of ependymoma, we focused on molecular alterations in ependymomas arising in the infratentorial compartment. Unsupervised clustering of available gene expression microarray data revealed two major subgroups of infratentorial ependymoma. Group 1 tumors over expressed genes that were associated with mesenchyme, Group 2 tumors showed no distinct gene ontologies. To assess the prognostic significance of these gene expression subgroups, real-time reverse transcriptase polymerase chain reaction assays were performed on genes defining the subgroups in a training set. This resulted in a 10-gene prognostic signature. Multivariate analysis showed that the 10-gene signature was an independent predictor of recurrence-free survival after adjusting for clinical factors. Evaluation of an external dataset describing subgroups of infratentorial ependymomas showed concordance of subgroup definition, including validation of the mesenchymal subclass. Importantly, the 10-gene signature was validated as a predictor of recurrence-free survival in this dataset. Taken together, the results indicate a link between clinical outcome and biologically identified subsets of infratentorial ependymoma and offer the potential for prognostic testing to estimate clinical aggressiveness in these tumors.
KeywordsInfratentorial ependymoma Expression profiling Gene expression signature Prognostic genes Microarray Biomarker
We thank the following individuals for their efforts in support of this work. From MD Anderson Cancer Center: Susan Cweren and Mary Jo Reyes; from the University of Pittsburgh Medical Center: Frank Lieberman, Ronald Hamilton, Regina Jakacki, Stephanie Bortoluzzi and Angela Krol; from the Children’s National Medical Center: Amulya Rao, and Ashley Hill; from the University of California, San Francisco: Ashley DeSilva; from St Jude Children’s Research Hospital: Letitia Williams and Annemarie McClellan; from Children’s Memorial Hospital: Kelly Verel and Nicole Reinholdt; from Cincinnati Children’s Hospital: Christine Minges, Lori Davis and Rebecca Turner; from Henry Ford Hospital: Lisa Scarpace; from Memorial Sloan Kettering Cancer Centre: Joseph Parks and Meredith Gondo; from University San Giovanni Battista Torino-Italy: Polly Graziani and Chiara Bosa. This work was supported by the Collaborative Ependymoma Research Network (CERN) Foundation and a SPORE in Brain Cancer grant from the NIH (5 P50 CA127001-03).
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