title: RB1 gene inactivation by chromothripsis in human retinoblastoma.
abstract: Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA. In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.
authors: Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Justina
authors: J
authors: McEvoy
authors: Panduka
authors: P
authors: Nagahawatte
authors: David
authors: D
authors: Finkelstein
authors: Jennifer
authors: J
authors: Richards-Yutz
authors: Marcus
authors: M
authors: Valentine
authors: Jing
authors: J
authors: Ma
authors: Charles
authors: C
authors: Mullighan
authors: Guangchun
authors: G
authors: Song
authors: Xiang
authors: X
authors: Chen
authors: Matthew
authors: M
authors: Wilson
authors: Rachel
authors: R
authors: Brennan
authors: Stanley
authors: S
authors: Pounds
authors: Jared
authors: J
authors: Becksfort
authors: Robert
authors: R
authors: Huether
authors: Charles
authors: C
authors: Lu
authors: Robert S
authors: RS
authors: Fulton
authors: Lucinda L
authors: LL
authors: Fulton
authors: Xin
authors: X
authors: Hong
authors: David J
authors: DJ
authors: Dooling
authors: Kerri
authors: K
authors: Ochoa
authors: Elaine R
authors: ER
authors: Mardis
authors: Richard K
authors: RK
authors: Wilson
authors: John
authors: J
authors: Easton
authors: Jinghui
authors: J
authors: Zhang
authors: James R
authors: JR
authors: Downing
authors: Arupa
authors: A
authors: Ganguly
authors: Michael A
authors: MA
authors: Dyer
mesh_terms: D002869:Chromosome Aberrations; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016161:Genes, Retinoblastoma; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019572:Retinal Neoplasms / Q000235:genetics*; D012175:Retinoblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; D016160:Retinoblastoma Protein