Expression Profiling of Ependymomas Unravels Localization and Tumor Grade-Specific Tumorigenesis

BACKGROUND: Ependymomas derive from ependymal cells that cover the cerebral ventricles and the central canal of the spinal cord. The molecular alterations leading to ependymomal oncogenesis are not completely understood. METHODS: The authors performed array-based expression profiling on a series of 34 frozen ependymal tumors with different localizations and histologic grades. Data were analyzed by non-supervised and supervised clustering methods along with Gene Ontology and Pathway Analyzer tools. RESULTS: Class discovery experiments indicated a strong correlation between profiles and tumor localization as well as World Health Organization (WHO) tumor grades. On the basis of supervised clustering, intracranial ependymomas were associated with high expression levels of Notch, Hedgehog, and bone morphogenetic protein pathway members. In contrast, most of the homeobox-containing genes manifested high expression in extracranial ependymomas. The results also revealed that WHO grade 2 ependymomas differed from WHO grade 3 ependymomas by genes implicated in Wnt/beta-catenin signaling, cell cycle, E2F transcription factor 1 destruction, angiogenesis, apoptosis, remodeling of adherens junctions, and mitotic spindle formation. CONCLUSIONS: Taken together, the tumor localization-related gene sets mainly implicated in stem cell maintenance, renewal, and differentiation suggest the dysregulation of localized cancer stem cells during ependymoma development. The WHO grade differentiating pathways suggested that alteration of the Wnt/beta-catenin signaling pathway is a key event in the tumorigenesis of WHO grade 3 ependymomas. On the basis of the current data, the authors suggest a developmental scheme of ependymomas that integrates tumor localization and tumor grades, and that pinpoints new targets for the development of future therapeutic approaches. Cancer 2009;115:3955-68. (C) 2009 American Cancer Society.