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A novel retinoblastoma therapy from genomic and epigenetic analyses

Author

Listed:
  • Jinghui Zhang

    (St Jude Children’s Research Hospital)

  • Claudia A. Benavente

    (St Jude Children’s Research Hospital)

  • Justina McEvoy

    (St Jude Children’s Research Hospital)

  • Jacqueline Flores-Otero

    (St Jude Children’s Research Hospital)

  • Li Ding

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Xiang Chen

    (St Jude Children’s Research Hospital)

  • Anatoly Ulyanov

    (St Jude Children’s Research Hospital)

  • Gang Wu

    (St Jude Children’s Research Hospital)

  • Matthew Wilson

    (University of Tennessee Health Science Center
    St Jude Children’s Research Hospital)

  • Jianmin Wang

    (Hartwell Center for Biotechnology & Bioinformatics, St Jude Children’s Research Hospital)

  • Rachel Brennan

    (St Jude Children’s Research Hospital)

  • Michael Rusch

    (St Jude Children’s Research Hospital)

  • Amity L. Manning

    (Massachusetts General Hospital)

  • Jing Ma

    (St Jude Children’s Research Hospital)

  • John Easton

    (St Jude Children’s Research Hospital)

  • Sheila Shurtleff

    (St Jude Children’s Research Hospital)

  • Charles Mullighan

    (St Jude Children’s Research Hospital)

  • Stanley Pounds

    (St Jude Children’s Research Hospital)

  • Suraj Mukatira

    (Hartwell Center for Biotechnology & Bioinformatics, St Jude Children’s Research Hospital)

  • Pankaj Gupta

    (Hartwell Center for Biotechnology & Bioinformatics, St Jude Children’s Research Hospital)

  • Geoff Neale

    (Hartwell Center for Biotechnology & Bioinformatics, St Jude Children’s Research Hospital)

  • David Zhao

    (St Jude Children’s Research Hospital)

  • Charles Lu

    (The Genome Institute, Washington University School of Medicine in St Louis)

  • Robert S. Fulton

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Lucinda L. Fulton

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Xin Hong

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • David J. Dooling

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Kerri Ochoa

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Clayton Naeve

    (St Jude Children’s Research Hospital)

  • Nicholas J. Dyson

    (Massachusetts General Hospital)

  • Elaine R. Mardis

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis
    Siteman Cancer Center, Washington University School of Medicine in St Louis)

  • Armita Bahrami

    (St Jude Children’s Research Hospital)

  • David Ellison

    (St Jude Children’s Research Hospital)

  • Richard K. Wilson

    (The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • James R. Downing

    (St Jude Children’s Research Hospital)

  • Michael A. Dyer

    (St Jude Children’s Research Hospital
    University of Tennessee Health Science Center
    Howard Hughes Medical Institute)

Abstract

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

Suggested Citation

  • Jinghui Zhang & Claudia A. Benavente & Justina McEvoy & Jacqueline Flores-Otero & Li Ding & Xiang Chen & Anatoly Ulyanov & Gang Wu & Matthew Wilson & Jianmin Wang & Rachel Brennan & Michael Rusch & Am, 2012. "A novel retinoblastoma therapy from genomic and epigenetic analyses," Nature, Nature, vol. 481(7381), pages 329-334, January.
    • Handle: RePEc:nat:nature:v:481:y:2012:i:7381:d:10.1038_nature10733
    DOI: 10.1038/nature10733
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    Cited by:

    1. Hong-Tao Li & Liya Xu & Daniel J. Weisenberger & Meng Li & Wanding Zhou & Chen-Ching Peng & Kevin Stachelek & David Cobrinik & Gangning Liang & Jesse L. Berry, 2022. "Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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