Splicing-Disrupting Mutations in Inherited Predisposition to Solid Pediatric Cancer

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.

Intronic Germline DICER1 Variants in Patients With Sertoli-Leydig Cell Tumor

“…Deep intronic variants have occasionally been reported in DICER1 , 18 , 19 and intronic pLOF variants arise in other cancer predisposition genes with varying frequency. 20 For example, splicing variants account for 20%-37% of pathogenic variants in NF1 . 21 - 23 In BRCA1 / 2 , intron sequencing of 192 families with hereditary breast and ovarian cancer without exonic pLOF variants identified a single pathogenic deep-intronic variant.…”