Journal
NATURE
Volume 506, Issue 7489, Pages 451-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13109
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Funding
- St. Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project
- National Institutes of Health [R01CA129541, P01CA96832, P30CA021765]
- Collaborative Ependymoma Research Network (CERN)
- American Lebanese Syrian Associated Charities (ALSAC)
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Members of the nuclear factor-kappa B (NF-kappa B) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kappa B signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kappa 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-kappa 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-kappa 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.
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