A Novel Retinoblastoma Therapy from Genomic and Epigenetic Analyses


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.

DOI: 10.1038/nature10733

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@inproceedings{Zhang2012ANR, title={A Novel Retinoblastoma Therapy from Genomic and Epigenetic Analyses}, author={Jinghui Zhang and Claudia A. Benavente and Justina McEvoy and Jacqueline Flores-Otero and Li Ding and Xiang Chen and Anatoly Ulyanov and Gang Wu and Matthew Wilson and Jianmin Wang and Rachel Brennan and Michael Rusch and Amity L. Manning and Jing Ma and John Easton and Sheila Shurtleff and Charles Mullighan and Stanley Pounds and Suraj Mukatira and Pankaj Gupta and Geoff Neale and David Zhao and Charles Lu and Robert S. Fulton and Lucinda L. Fulton and Xin Hong and David J. Dooling and Kerri Ochoa and Clayton Naeve and Nicholas J Dyson and Elaine R. Mardis and Armita Bahrami and David Ellison and Richard K. Wilson and James Downing and Michael A. Dyer}, booktitle={Nature}, year={2012} }