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 GuptaGeoff 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, Michael A. Dyer

Research output: Contribution to journalArticle

259 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)329-334
Number of pages6
JournalNature
Volume481
Issue number7381
DOIs
StatePublished - Jan 19 2012

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Retinoblastoma
Epigenomics
Neoplasms
Retinal Neoplasms
Therapeutics
Genome
Proto-Oncogenes
Genomic Instability
Neoplasm Genes
Cell Survival
Cell Death
Mutation

All Science Journal Classification (ASJC) codes

  • General

Cite this

Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., ... Dyer, M. A. (2012). A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature, 481(7381), 329-334. https://doi.org/10.1038/nature10733

A novel retinoblastoma therapy from genomic and epigenetic analyses. / Zhang, Jinghui; Benavente, Claudia A.; McEvoy, Justina; Flores-Otero, Jacqueline; Ding, Li; Chen, Xiang; Ulyanov, Anatoly; Wu, Gang; Wilson, Matthew; Wang, Jianmin; Brennan, Rachel; Rusch, Michael; Manning, Amity L.; Ma, Jing; Easton, John; Shurtleff, Sheila; Mullighan, Charles; Pounds, Stanley; Mukatira, Suraj; Gupta, Pankaj; Neale, Geoff; Zhao, David; Lu, Charles; Fulton, Robert S.; Fulton, Lucinda L.; Hong, Xin; Dooling, David J.; Ochoa, Kerri; Naeve, Clayton; Dyson, Nicholas J.; Mardis, Elaine R.; Bahrami, Armita; Ellison, David; Wilson, Richard K.; Downing, James R.; Dyer, Michael A.

In: Nature, Vol. 481, No. 7381, 19.01.2012, p. 329-334.

Research output: Contribution to journalArticle

Zhang, J, Benavente, CA, McEvoy, J, Flores-Otero, J, Ding, L, Chen, X, Ulyanov, A, Wu, G, Wilson, M, Wang, J, Brennan, R, Rusch, M, Manning, AL, Ma, J, Easton, J, Shurtleff, S, Mullighan, C, Pounds, S, Mukatira, S, Gupta, P, Neale, G, Zhao, D, Lu, C, Fulton, RS, Fulton, LL, Hong, X, Dooling, DJ, Ochoa, K, Naeve, C, Dyson, NJ, Mardis, ER, Bahrami, A, Ellison, D, Wilson, RK, Downing, JR & Dyer, MA 2012, 'A novel retinoblastoma therapy from genomic and epigenetic analyses', Nature, vol. 481, no. 7381, pp. 329-334. https://doi.org/10.1038/nature10733
Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 2012 Jan 19;481(7381):329-334. https://doi.org/10.1038/nature10733
Zhang, Jinghui ; Benavente, Claudia A. ; McEvoy, Justina ; Flores-Otero, Jacqueline ; Ding, Li ; Chen, Xiang ; Ulyanov, Anatoly ; Wu, Gang ; Wilson, Matthew ; Wang, Jianmin ; Brennan, Rachel ; Rusch, Michael ; Manning, Amity L. ; Ma, Jing ; Easton, John ; Shurtleff, Sheila ; Mullighan, Charles ; Pounds, Stanley ; Mukatira, Suraj ; Gupta, Pankaj ; Neale, Geoff ; Zhao, David ; Lu, Charles ; Fulton, Robert S. ; Fulton, Lucinda L. ; Hong, Xin ; Dooling, David J. ; Ochoa, Kerri ; Naeve, Clayton ; Dyson, Nicholas J. ; Mardis, Elaine R. ; Bahrami, Armita ; Ellison, David ; Wilson, Richard K. ; Downing, James R. ; Dyer, Michael A. / A novel retinoblastoma therapy from genomic and epigenetic analyses. In: Nature. 2012 ; Vol. 481, No. 7381. pp. 329-334.
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