A novel retinoblastoma therapy from genomic and epigenetic analyses

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, Amity L. Manning, Jing Ma, John Easton, Sheila Shurtleff, Charles Mullighan, Stanley Pounds, Suraj Mukatira, Pankaj Gupta, Geoff Neale, David Zhao, Charles Lu, Robert S. Fulton, Lucinda L. Fulton, Xin Hong, David J. Dooling, Kerri Ochoa, Clayton Naeve, Nicholas J. Dyson, Elaine R. Mardis, Armita Bahrami, David Ellison, Richard K. Wilson (), James R. Downing () and Michael A. Dyer ()
Additional contact information
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
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
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
Lucinda L. Fulton: The Genome Institute, Washington University School of Medicine in St Louis
Xin Hong: The Genome Institute, Washington University School of Medicine in St Louis
David J. Dooling: The Genome Institute, Washington University School of Medicine in St Louis
Kerri Ochoa: The Genome Institute, 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
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
James R. Downing: St Jude Children’s Research Hospital
Michael A. Dyer: St Jude Children’s Research Hospital

Nature, 2012, vol. 481, issue 7381, 329-334

Abstract: 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.

Date: 2012
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/nature10733 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:481:y:2012:i:7381:d:10.1038_nature10733

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature10733

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().