RB1 gene inactivation by chromothripsis in human retinoblastoma

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 nove...

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Vydané v:Oncotarget Ročník 5; číslo 2; s. 438
Hlavní autori: McEvoy, Justina, Nagahawatte, Panduka, Finkelstein, David, Richards-Yutz, Jennifer, Valentine, Marcus, Ma, Jing, Mullighan, Charles, Song, Guangchun, Chen, Xiang, Wilson, Matthew, Brennan, Rachel, Pounds, Stanley, Becksfort, Jared, Huether, Robert, Lu, Charles, Fulton, Robert S, Fulton, Lucinda L, Hong, Xin, Dooling, David J, Ochoa, Kerri, Mardis, Elaine R, Wilson, Richard K, Easton, John, Zhang, Jinghui, Downing, James R, Ganguly, Arupa, Dyer, Michael A
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 30.01.2014
Predmet:
Chromosome Aberrations
Gene Expression
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Retinoblastoma
Humans
Oncogene Proteins - genetics
Oncogene Proteins - metabolism
Retinal Neoplasms - genetics
Retinoblastoma - genetics
Retinoblastoma - metabolism
Retinoblastoma - pathology
Retinoblastoma Protein - genetics
Retinoblastoma Protein - metabolism
ISSN:1949-2553, 1949-2553
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Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.1686