A novel retinoblastoma therapy from genomic and epigenetic analyses

Autor: James R. Downing, Kerri Ochoa, Michael Rusch, Jacqueline Flores-Otero, Jinghui Zhang, Anatoly Ulyanov, Jianmin Wang, Stanley Pounds, Sheila A. Shurtleff, Pankaj Gupta, Gang Wu, Justina McEvoy, Xiang Chen, David H. Ellison, Xin Hong, Richard K. Wilson, Li Ding, Amity L. Manning, David J. Dooling, Lucinda Fulton, Geoff Neale, Suraj Mukatira, Charles Lu, Matthew W. Wilson, David Zhao, Nicholas J. Dyson, Armita Bahrami, Elaine R. Mardis, Clayton W. Naeve, John Easton, Robert S. Fulton, Charles G. Mullighan, Michael A. Dyer, Rachel C. Brennan, Jing Ma, Claudia A. Benavente
Rok vydání: 2012
Předmět:
Syk
medicine.disease_cause
Proto-Oncogene Mas
Retinoblastoma Protein
Epigenesis
Genetic
Mice
0302 clinical medicine
Chromosome instability
2.1 Biological and endogenous factors
Molecular Targeted Therapy
Aetiology
Genes
Retinoblastoma
Cancer
Pediatric
Regulation of gene expression
0303 health sciences
Mutation
Multidisciplinary
Cell Death
Retinoblastoma
Intracellular Signaling Peptides and Proteins
Retinoblastoma protein
Genomics
Protein-Tyrosine Kinases
3. Good health
Gene Expression Regulation
Neoplastic
030220 oncology & carcinogenesis
Sequence Analysis
Biotechnology
Pediatric Cancer
Cell Survival
General Science & Technology
Biology
Cell Line
03 medical and health sciences
Rare Diseases
Genetic
Chromosomal Instability
Genetics
medicine
Animals
Humans
Syk Kinase
Epigenetics
Eye Disease and Disorders of Vision
Protein Kinase Inhibitors
030304 developmental biology
Neoplastic
Human Genome
Sequence Analysis
DNA
DNA
Aneuploidy
medicine.disease
Xenograft Model Antitumor Assays
eye diseases
Gene Expression Regulation
Genes
biology.protein
Cancer research
Epigenesis
Zdroj: Nature, vol 481, iss 7381
ISSN: 1476-4687
0028-0836
Popis: 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.
Databáze: OpenAIRE
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