Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care

Simple Summary: The idea that motivated the design of the project is to offer a genetic germline analysis to all pediatric patients diagnosed in our pediatric oncology unit. The main objective is to determine the incidence of predisposing genetic variants when studying a cohort of pediatric cancer patients using an NGS gene panel. The custom panel employed is designed to detect variants in a large number of genes involved in pediatric cancer in order to be able to identify new genotype-phenotype relationships. The data obtained are valuable for estimating the incidence of predisposing genetic alterations, due to the large number of pediatric patients included in the study. Furthermore, the novel results collected in the main document, which suggest the involvement of new genes in the predisposition to different oncological diseases, are worthwhile.Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient's tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low.

Automated summary

The project aims to offer genetic germline analysis to all pediatric cancer patients in order to identify predisposing genetic variants and explore new genotype-phenotype relationships. The study found a significant incidence of predisposing genetic alterations in pediatric cancer patients and highlights the need for expert genetic counseling in identifying such variants. The results confirm the importance of ongoing research on genetic predisposition in pediatric oncology and the utility of genetic screening tools for early detection and management.