A novel retinoblastoma therapy from genomic and epigenetic analyses

• Published in: Nature (London) Vol. 481; no. 7381; pp. 329 - 334
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.01.2012; Nature Publishing Group
• Subjects: 631/208/2489/2487/2486; 631/208/69; 631/67/1059/602; 631/67/1484; Aneuploidy; Animals; Apoptosis; Biological and medical sciences; Cancer; Cell Death - drug effects; Cell Line; Cell Survival - drug effects; Children & youth; Chromosomal Instability - genetics; Chromosomes; Deregulation; Development and progression; Diagnosis; DNA methylation; Epigenesis, Genetic - genetics; Epigenetics; Experiments; Gene Expression Regulation, Neoplastic; Gene mutations; Gene therapy; Genes, Retinoblastoma - genetics; Genetic aspects; Genomes; Genomics; Health aspects; Human subjects; Humanities and Social Sciences; Humans; Inactivation; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Medical sciences; Mice; Molecular Targeted Therapy; multidisciplinary; Mutation; Mutation - genetics; Ophthalmology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Mas; Retinoblastoma; Retinoblastoma - drug therapy; Retinoblastoma - genetics; Retinoblastoma - pathology; Retinoblastoma Protein - deficiency; Retinoblastoma Protein - genetics; Risk factors; Science; Science (multidisciplinary); Sequence Analysis, DNA; Studies; Syk Kinase; Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus; Xenograft Model Antitumor Assays; United States; Human; Nervous system diseases; Retinopathy; Retinoblastoma gene; Targeted therapy; Malignant tumor; Genetic instability; Eye disease; Treatment; C-Onc gene; Epigenetics; Genetics; Tyrosine protein kinase Syk; Mutation; Genome; Retinoblastoma; Child; Protooncogene; Cancer; Tumor suppressor gene
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10733

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. The retinoblastoma genome is shown to be stable, but multiple cancer pathways are identified that are epigenetically deregulated, providing potential new therapeutic targets. SYK is a target in retinoblastoma Retinoblastoma is a rare and aggressive childhood cancer of the retina caused by loss of the RB1 gene. Whole-genome sequencing of four retinoblastomas now shows that the retinoblastoma genome is relatively stable, with a mutational rate among the lowest reported in human cancers and a remarkable lack of mutations in other tumour suppressor/oncogenic pathways. However, RB1 loss is associated with epigenetic deregulation of several cancer pathways. Significantly, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. A small-molecule inhibitor of SYK induced retinoblastoma tumour cell death in vitro and in vivo .