C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.

Abstract:: Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.

Authors:: M Parker, KM Mohankumar, C Punchihewa, R Weinlich, JD Dalton, Y Li, R Lee, RG Tatevossian, TN Phoenix, R Thiruvenkatam, E White, B Tang, W Orisme, K Gupta, M Rusch, X Chen, Y Li, P Nagahawhatte, E Hedlund, D Finkelstein, G Wu, S Shurtleff, J Easton, K Boggs, D Yergeau, B Vadodaria, HL Mulder, J Becksfort, P Gupta, R Huether, J Ma, G Song, A Gajjar, T Merchant, F Boop, AA Smith, L Ding, C Lu, K Ochoa, D Zhao, RS Fulton, LL Fulton, ER Mardis, RK Wilson, JR Downing, DR Green, J Zhang, DW Ellison, RJ Gilbertson

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