Non-Synonymous, Synonymous, and Non-Coding Nucleotide Variants Contribute to Recurrently Altered Biological Processes During Retinoblastoma Progression (original) (raw)

Retinoblastomas form in response to biallelicRB1mutations orMYCNamplification and progress to more aggressive and therapy-resistant phenotypes through accumulation of secondary genomic changes. Progression-related changes include recurrent somatic copy number alterations and typically non-recurrent nucleotide variants, including synonymous and non-coding variants, whose significance has been unclear. To assess synonymous and non-coding variant contributions to recurrently altered processes, we identified altered genes and over-represented variant gene ontologies in 168 exome or whole-genome-sequenced retinoblastomas and 12 tumor-matched cell lines. In addition to initiatingRB1mutations,MYCNamplification, and established retinoblastoma SCNAs, the analyses revealed enrichment of variant genes related to diverse biological processes including histone monoubiquitination, mRNA processing (P) body assembly, and mitotic sister chromatid segregation and cytokinesis. Importantly, inclusion o...