Publication

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

Nature. 2014 Feb 27;506(7489):451-5. doi: 10.1038/nature13109. Epub 2014 Feb 19.

Abstract

Members of the nuclear factor-?B (NF-?B) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-?B signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-?B 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-?B 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-?B 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

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