title: 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.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [3].
authors.forename: Matthew
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authors.lastname: Parker
authors.affiliation: 1] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2].
authors.forename: Kumarasamypet M
authors.initials: KM
authors.lastname: Mohankumar
authors.affiliation: 1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2].
authors.forename: Chandanamali
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authors.lastname: Punchihewa
authors.affiliation: 1] Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2].
authors.forename: Ricardo
authors.initials: R
authors.lastname: Weinlich
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Dalton
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lee
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Tatevossian
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Phoenix
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Thiruvenkatam
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Elsie
authors.initials: E
authors.lastname: White
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Wilda
authors.initials: W
authors.lastname: Orisme
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Kirti
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rusch
authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Panduka
authors.initials: P
authors.lastname: Nagahawhatte
authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Hedlund
authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Sheila
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authors.lastname: Shurtleff
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: John
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authors.lastname: Easton
authors.affiliation: St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.
authors.forename: Kristy
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authors.lastname: Boggs
authors.affiliation: St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.
authors.forename: Donald
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authors.lastname: Yergeau
authors.affiliation: St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.
authors.forename: Bhavin
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authors.lastname: Vadodaria
authors.affiliation: St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Mulder
authors.forename: Jared
authors.initials: J
authors.lastname: Becksfort
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Becksford
authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Pankaj
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authors.lastname: Gupta
authors.affiliation: Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Robert
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authors.lastname: Huether
authors.affiliation: St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.
authors.forename: Jing
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authors.lastname: Ma
authors.affiliation: St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.
authors.forename: Guangchun
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authors.lastname: Song
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.affiliation: Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Merchant
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Frederick
authors.initials: F
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authors.affiliation: MD Anderson Cancer Center Orlando, Pediatric Hematology/Oncology, 92 West Miller MP 318, Orlando, Florida 32806, USA.
authors.forename: Amy A
authors.initials: AA
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Charles
authors.initials: C
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Kerri
authors.initials: K
authors.lastname: Ochoa
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: David
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA.
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authors.initials: RS
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Lucinda L
authors.initials: LL
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [4] Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA.
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authors.initials: ER
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [4] Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Richard K
authors.initials: RK
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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authors.initials: JR
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authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Douglas R
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004806:Ependymoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D011506:Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C585140:ZFTA protein, human; C498143:RELA protein, human; C088374:YAP1 protein, human