C11orf95–RELA fusions drive oncogenic.pdf

ARTICLE doi:10.1038/nature13109 C11orf95–RELA fusions drive oncogenic NF-kB signalling in ependymoma Matthew Parker1,2*, Kumarasamypet M. Mohankumar3*, Chandanamali Punchihewa4*, Ricardo Weinlich5*, James D. Dalton1,4, Yongjin Li1,2, Ryan Lee4, Ruth G. Tatevossian1,4, Timothy N. Phoenix3, Radhika Thiruvenkatam3, Elsie White3, Bo Tang1,4, Wilda Orisme1,4, Kirti Gupta4, Michael Rusch2, Xiang Chen2, Yuxin Li2,6, Panduka Nagahawhatte2, Erin Hedlund2, David Finkelstein2, Gang Wu2, Sheila Shurtleff4, John Easton1,4, Kristy Boggs1, Donald Yergeau1, Bhavin Vadodaria1, Heather L. Mulder1, Jared Becksford4, Pankaj Gupta2, Robert Huether6, Jing Ma1, Guangchun Song1, Amar Gajjar1,7, Thomas Merchant8, Frederick Boop9, Amy A. Smith10, Li Ding1,11,12, Charles Lu1,11, Kerri Ochoa1,11,12, David Zhao1,2, Robert S. Fulton1,11, Lucinda L. Fulton1,11,12, Elaine R. Mardis1,11,12,13, Richard K. Wilson1,11,12,13, James R. Downing1,4, Douglas R. Green5, Jinghui Zhang1,2, David W. Ellison1,4 Richard J. Gilbertson1,3 Members of the nuclear factor-kB (NF-kB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kB activity in cancer. Here we show thatmore than two-thirds of supratentorial ependymomas contain oncogenic fusions betweenRELA, the principal effector of canonical NF-kB 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-kB 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 su