• A Corrigendum to this article was published on 23 April 2014

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, C11orf95RELA 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.

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Data deposits

Sequence and array data were deposited in the European Bioinformatics Institute (EBI) under accession number EGAS00001000254.

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Acknowledgements

This research was supported as part of the St. Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project. This work was supported by grants from the National Institutes of Health (R01CA129541, P01CA96832 and P30CA021765 to R.J.G), the Collaborative Ependymoma Research Network (CERN), and by the American Lebanese Syrian Associated Charities (ALSAC). We are grateful to S. Temple for the gift of reagents and the staff of the Hartwell Center for Bioinformatics and Biotechnology, Animal Imaging Center, and Flow Cytometry and Cell Sorting Shared Resource at St. Jude Children’s Research Hospital for technical assistance.

Author information

Author notes

    • Matthew Parker
    • , Kumarasamypet M. Mohankumar
    • , Chandanamali Punchihewa
    •  & Ricardo Weinlich

    These authors contributed equally to this work.

Affiliations

  1. St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA

    • Matthew Parker
    • , James D. Dalton
    • , Yongjin Li
    • , Ruth G. Tatevossian
    • , Bo Tang
    • , Wilda Orisme
    • , John Easton
    • , Kristy Boggs
    • , Donald Yergeau
    • , Bhavin Vadodaria
    • , Heather L. Mulder
    • , Jing Ma
    • , Guangchun Song
    • , Amar Gajjar
    • , Li Ding
    • , Charles Lu
    • , Kerri Ochoa
    • , David Zhao
    • , Robert S. Fulton
    • , Lucinda L. Fulton
    • , Elaine R. Mardis
    • , Richard K. Wilson
    • , James R. Downing
    • , Jinghui Zhang
    • , David W. Ellison
    •  & Richard J. Gilbertson
  2. Department of Computational Biology and Bioinformatics, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Matthew Parker
    • , Yongjin Li
    • , Michael Rusch
    • , Xiang Chen
    • , Yuxin Li
    • , Panduka Nagahawhatte
    • , Erin Hedlund
    • , David Finkelstein
    • , Gang Wu
    • , Jared Becksfort
    • , Pankaj Gupta
    • , David Zhao
    •  & Jinghui Zhang
  3. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Kumarasamypet M. Mohankumar
    • , Timothy N. Phoenix
    • , Radhika Thiruvenkatam
    • , Elsie White
    •  & Richard J. Gilbertson
  4. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Chandanamali Punchihewa
    • , James D. Dalton
    • , Ryan Lee
    • , Ruth G. Tatevossian
    • , Bo Tang
    • , Wilda Orisme
    • , Kirti Gupta
    • , Sheila Shurtleff
    • , John Easton
    • , James R. Downing
    •  & David W. Ellison
  5. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Ricardo Weinlich
    •  & Douglas R. Green
  6. Structural Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Yuxin Li
    •  & Robert Huether
  7. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Amar Gajjar
  8. Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Thomas Merchant
  9. Department of Surgery, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Frederick Boop
  10. MD Anderson Cancer Center Orlando, Pediatric Hematology/Oncology, 92 West Miller MP 318, Orlando, Florida 32806, USA

    • Amy A. Smith
  11. The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA

    • Li Ding
    • , Charles Lu
    • , Kerri Ochoa
    • , Robert S. Fulton
    • , Lucinda L. Fulton
    • , Elaine R. Mardis
    •  & Richard K. Wilson
  12. Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA

    • Li Ding
    • , Kerri Ochoa
    • , Lucinda L. Fulton
    • , Elaine R. Mardis
    •  & Richard K. Wilson
  13. Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA

    • Elaine R. Mardis
    •  & Richard K. Wilson

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Contributions

M.P., K.M.M., C.P., R.W., J.D.D., R.L., R.G.T., T.N.P., R.T., E.W., B.T., W.O., K.G., M.R., X.C., P.N., E.H., D.F., G.W., S.S., J.E., K.B., D.Y., B.V., H.L.M., J.B., P.G., R.H., J.M., G.S., L.D., C.L., K.O., D.Z., R.S.F., L.L.F. Yo.L., Yu.L., A.G., A.A.S., F.B. and T.M. contributed to the design and conduct of experiments and to the writing. E.R.M., R.K.W., J.R.D. and D.R.G. contributed to experimental design and to the writing. J.Z., D.W.E. and R.J.G. conceived the research and designed, directed and wrote the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jinghui Zhang or David W. Ellison or Richard J. Gilbertson.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Methods and Materials, Supplementary Results, Supplementary Figures 1-15 additional references.

Zip files

  1. 1.

    Supplementary Tables

    This file contains Supplementary Tables 1-6 and comprises Table 1: Clinical, pathological and validated genetic abnormalities of all 177 tumors in the study cohort ; Table 2: Coverage data for tumours analyzed by whole genome sequencing; Table 3: Coverage data for tumors analyzed by RNASeq; able 4: Tier 1 validated and putative high quality SNV and indel mutations; Table 5: Tier 2 validated and putative high quality SNV and indel mutations; and Table S6: Tier 3 validated and putative high-quality SNVs and indel mutations.

  2. 2.

    Supplementary Tables

    This file contains Supplementary Tables 7-12 and comprises Table 7: Numbers of high quality validated and putative Tier1 SNVs and indel mutations detected by WGS; Table 8: Copy number variations in tumors from the discovery series analyzed by WGS; Table 9: Copy number alterations detected by SNP 6 arrays; Table 10: Summary of All Genetic Aberrations Found by WGS; Table 11: Counts of structural variations detected by CREST in samples analyzed by WGS; and Table 12: Statistical analysis of chromothripsis status within 11q13.1.

  3. 3.

    Supplementary Tables

    This file contains Supplementary Tables 13-18 and comprises Table 13: Validated and uncovered fusion builder predictions from WGS; Table 14: Primers used for SV validation; Table 15: iFISH probes; Table 16a: C11orf95-RELA fusions predicted by RNA-seq; Table 16b: Fusions involving C11orf95 but not RELA; Table 16c: Additional fusions not involving C11orf95; Table 17a: Significantly activated transcription regulators identified by Ingenuity Pathway Analysis; Table 17b: Significant networks identified by analysis of differential gene expression data or RNASeq data & highlighting NF-kB; Table 18a: Pathway analysis of genes upregulated by RELAWT in NSCs and Table 18b: Pathway analysis of genes upregulated by RELAFUS1 in NSCs

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https://doi.org/10.1038/nature13109

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