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

Matthew Parker, Kumarasamypet M. Mohankumar, Chandanamali Punchihewa, Ricardo Weinlich, James D. Dalton, Yongjin Li, Ryan Lee, Ruth G. Tatevossian, Timothy N. Phoenix, Radhika Thiruvenkatam, Elsie White, Bo Tang, Wilda Orisme, Kirti Gupta, Michael Rusch, Xiang Chen, Yuxin Li, Panduka Nagahawhatte, Erin Hedlund, David Finkelstein, Gang Wu, Sheila Shurtleff, John Easton, Kristy Boggs, Donald Yergeau, Bhavin Vadodaria, Heather L. Mulder, Jared Becksfort, Pankaj Gupta, Robert Huether, Jing Ma, Guangchun Song, Amar Gajjar, Thomas Merchant, Frederick Boop, Amy A. Smith, Li Ding, Charles Lu, Kerri Ochoa, David Zhao, Robert S. Fulton, Lucinda L. Fulton, Elaine R. Mardis, Richard K. Wilson, James R. Downing, Douglas R. Green, Jinghui Zhang (), David W. Ellison () and Richard J. Gilbertson ()
Additional contact information
Matthew Parker: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Kumarasamypet M. Mohankumar: St. Jude Children’s Research Hospital
Chandanamali Punchihewa: St. Jude Children’s Research Hospital
Ricardo Weinlich: St. Jude Children’s Research Hospital
James D. Dalton: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Yongjin Li: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Ryan Lee: St. Jude Children’s Research Hospital
Ruth G. Tatevossian: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Timothy N. Phoenix: St. Jude Children’s Research Hospital
Radhika Thiruvenkatam: St. Jude Children’s Research Hospital
Elsie White: St. Jude Children’s Research Hospital
Bo Tang: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Wilda Orisme: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Kirti Gupta: St. Jude Children’s Research Hospital
Michael Rusch: St. Jude Children’s Research Hospital
Xiang Chen: St. Jude Children’s Research Hospital
Yuxin Li: St. Jude Children’s Research Hospital
Panduka Nagahawhatte: St. Jude Children’s Research Hospital
Erin Hedlund: St. Jude Children’s Research Hospital
David Finkelstein: St. Jude Children’s Research Hospital
Gang Wu: St. Jude Children’s Research Hospital
Sheila Shurtleff: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Kristy Boggs: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Donald Yergeau: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Bhavin Vadodaria: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Heather L. Mulder: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Jared Becksfort: St. Jude Children’s Research Hospital
Pankaj Gupta: St. Jude Children’s Research Hospital
Robert Huether: Structural Biology, St. Jude Children’s Research Hospital
Jing Ma: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Guangchun Song: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Amar Gajjar: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Thomas Merchant: St. Jude Children’s Research Hospital
Frederick Boop: St. Jude Children’s Research Hospital
Amy A. Smith: MD Anderson Cancer Center Orlando, Pediatric Hematology/Oncology, 92 West Miller MP 318, Orlando, Florida 32806, USA
Li Ding: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Charles Lu: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Kerri Ochoa: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
David Zhao: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Robert S. Fulton: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Lucinda L. Fulton: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Elaine R. Mardis: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Richard K. Wilson: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
James R. Downing: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Douglas R. Green: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
David W. Ellison: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project
Richard J. Gilbertson: St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project

Nature, 2014, vol. 506, issue 7489, 451-455

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13109

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