PM-15 * C11orf95-RELA FUSION ALONE IS SUFFICIENT TO FORM HUMAN SUPRATENTORIAL EPENDYMOMA-LIKE TUMOR IN MICE

Abstract

Ependymomas (EMs) are primary tumors of the central nervous system that preferentially occur in children. Recent deep molecular analyses have revealed that these tumors are divided into molecularly distinct subgroups; particularly supra- and infratentorial EMs have significantly different genetic alterations. Chromothripsis is a massive genomic rearrangement event rarely occurring in various types of tumors, potentially resulting in oncogenic gene fusion. Recently, several types of C11orf95-associated fusion gene caused by gene rearrangements via chromothripsis were identified in a large fraction of supratentorial EMs. These fusion genes have been shown to be oncogenic when transferred to CNS stem cells in allograft model, these fusion genes may be promising therapeutic targets for the tumor type. Pysiologically relevant genetic mouse models are useful for the understanding of oncogenic mechanisms and drivers and for the exploration of theraputic targets in particular tumor types. Therefore, we used the RCAS/tv-a system to determine the ability for the C11orf95-RELA fusion to induce the formation of ependymomas in vivo in mice. When RCAS vector expressing the C11orf95-RELA fusion was introduced into Nestin/tv-a mice, tumors formed in a few months. Additional Cdkn2a loss in the context leads to an increased tumor penetrance. These tumors were observed as a circumscribed tumor adjacent to ventricular surface and formed abundant branching vascular network in the tumor, likely recapitulating histologic features of the human counterpart. This model should be a useful tool for understanding EM biology, therapeutic response, and recurrence.