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.
authors.affiliation: Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Benavente
authors.forename: Justina
authors.initials: J
authors.lastname: McEvoy
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Flores-Otero
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Anatoly
authors.initials: A
authors.lastname: Ulyanov
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Matthew
authors.initials: M
authors.lastname: Wilson
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Rachel
authors.initials: R
authors.lastname: Brennan
authors.forename: Michael
authors.initials: M
authors.lastname: Rusch
authors.forename: Amity L
authors.initials: AL
authors.lastname: Manning
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: John
authors.initials: J
authors.lastname: Easton
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.forename: Charles
authors.initials: C
authors.lastname: Mullighan
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Suraj
authors.initials: S
authors.lastname: Mukatira
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Geoff
authors.initials: G
authors.lastname: Neale
authors.forename: David
authors.initials: D
authors.lastname: Zhao
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.forename: Lucinda L
authors.initials: LL
authors.lastname: Fulton
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.forename: David J
authors.initials: DJ
authors.lastname: Dooling
authors.forename: Kerri
authors.initials: K
authors.lastname: Ochoa
authors.forename: Clayton
authors.initials: C
authors.lastname: Naeve
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Armita
authors.initials: A
authors.lastname: Bahrami
authors.forename: David
authors.initials: D
authors.lastname: Ellison
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000782:Aneuploidy; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D043171:Chromosomal Instability / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma / Q000235:genetics; D023281:Genomics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D012175:Retinoblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics; D017422:Sequence Analysis, DNA; D000072377:Syk Kinase; D023041:Xenograft Model Antitumor Assays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D016160:Retinoblastoma Protein; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse