Identification of driver genes with aberrantly alternative splicing events in pediatric patients with retinoblastoma

Retinoblastoma (RB) is one of the most common cancer in children. However, the specific mechanism about RB tumorigenesis has not been fully understood. In this study, to comprehensively characterize the splicing alterations in the tumorigenesis of RB, we analyzed the differential alternative splicing events in RB. Specifically, the isoforms of RB1 were downregulated in the RB samples, and a large proportion of differentially expressed genes had multiple differentially expressed transcripts (64%). We identified 1453 genes with differential alternative splicing, among which, SE accounted for the majority, followed by MXE, RI, A3SS, and A5SS. Furthermore, the biological function related to the normal function of eyes, and E2F family TFs were significantly enriched by the genes with differential alternative splicing. Among the genes associated with visual sense, ABCA4 was found to have two mutually exclusive exons, resulting in two isoforms with different functionalities. Notably, DAZAP1 was identified as one of the critical splicing factors in RB, which was potentially involved in E2F and RB pathways. Functionally, differential binding sites in DAZAP1 protein were significantly observed between RB and normal samples. Based on the comprehensive analysis of the differential alternative splicing events and splicing factors, we identified some driver genes with differential alternative splicing and critical splicing factors involved in RB, which would greatly improve our understanding of the alternative splicing process in the tumorigenesis of RB.