Splicing-Disrupting Mutations in Inherited Predisposition to Solid Pediatric Cancer

SIMPLE SUMMARY: Until recently, the prevalence of hereditary cancer in children was estimated to be very low. However, recent studies suggest that at least 10% of pediatric cancer patients have a germline mutation in a cancer predisposition gene. It has been shown that most of these mutations affect splicing, a process by which different transcripts of the same gene are produced. The splicing process is very important, as it regulates many aspects of cellular proliferation, survival, and differentiation. Hereditary cancer genes are highly prone to splicing alterations, and among them there are several genes that may contribute to the development of pediatric solid tumors when mutated in the germline. In this review, we analyze the importance of the splicing-disrupting mutations in pediatric solid cancer and inherited predisposition syndromes. The therapies developed to correct aberrant splicing in cancer are also discussed. ABSTRACT: The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an increased risk of hereditary cancer are variants affecting splicing. RNA splicing is an essential process involved in different cellular processes such as proliferation, survival, and differentiation, and alterations in this pathway have been implicated in many human cancers. Hereditary cancer genes are highly susceptible to splicing mutations, and among them there are several genes that may contribute to pediatric solid tumors when mutated in the germline. In this review, we have focused on the analysis of germline splicing-disrupting mutations found in pediatric solid tumors, as the discovery of pathogenic splice variants in pediatric cancer is a growing field for the development of personalized therapies. Therapies developed to correct aberrant splicing in cancer are also discussed as well as the options to improve the diagnostic yield based on the increase in the knowledge in splicing.