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.