@article{3edfee5a3a9e41e8bfdb99a4a4f5a1c1,
title = "A novel retinoblastoma therapy from genomic and epigenetic analyses",
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.",
author = "Jinghui Zhang and Benavente, {Claudia A.} 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 Manning, {Amity L.} 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 Fulton, {Robert S.} and Fulton, {Lucinda L.} and Xin Hong and Dooling, {David J.} and Kerri Ochoa and Clayton Naeve and Dyson, {Nicholas J.} and Mardis, {Elaine R.} and Armita Bahrami and David Ellison and Wilson, {Richard K.} and Downing, {James R.} and Dyer, {Michael A.}",
note = "Funding Information: Acknowledgements The WGS was supported as part of the St Jude Children{\textquoteright}s Research Hospital – Washington University Pediatric Cancer Genome Project. We thank J. Lahti, J. Dalton and M. Valentine for help with FISH analysis, L. Holmfeldt, J. Zhang and M. Barbato for help with sample preparation, and V. Valentine for spectral karyotype analysis. We thank I. Qaddoumi, C. Rodriguez-Galindo and B. Haik for the support of the St Jude Children{\textquoteright}s Research Hospital retinoblastoma clinical research and W. Lei, D. McGoldrick, D. Alford, S. Espy, J. Obenauer and K. Johnson for assistance with data acquisition, handling and analysis. We thank A. McArthur and C. Guess for editing the manuscript, J. Temirov for help with sister chromatid analysis, J. Thurman for help with histology, F. Krafcik for help with cell culture, J. Wu and C. Billups for statistical analysis, J. Jeon for help with lentiviral preparations and C. Bradley for assistance with preclinical testing. This work was supported, in part, by Cancer Center Support (CA21765) from the NCI; grants to M.A.D. from the NIH (EY014867 and EY018599), the American Cancer Society and the Research to Prevent Blindness Foundation; and the American Lebanese Syrian Associated Charities. M.A.D. is a Howard Hughes Medical Institute Early Career Scientist. This work was also supported byanAmericanCancer Society Fellowship toA.L.M.,the MGH Cancer Center Saltonstall Foundation Scholarship to N.J.D. and funding from AstraZeneca and NIH grants GM81607 and CA64402 to N.J.D.",
year = "2012",
month = jan,
day = "19",
doi = "10.1038/nature10733",
language = "English (US)",
volume = "481",
pages = "329--334",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7381",
}