Identification of Altered Primary Immunodeficiency-Associated Genes and Their Implications in Pediatric Cancers

SIMPLE SUMMARY: In children, cancer remains the most common cause of disease-related mortality and is responsible for more deaths from infancy through adolescence than any other disease. Malignancies are observed more frequently in individuals with primary immunodeficiencies (PID), and cancer is one of the most common causes of death in patients with PIDs. However, the molecular mechanisms that link the immune function to malignancy development remain poorly understood. The primary aim of this project was to identify and highlight the molecular mechanisms by which PID-related genes may lead to the development of pediatric cancers and was completed using a novel bioinformatics framework. This study highlighted multiple PID-related genes for further investigation regarding their implications in PIDs and pediatric cancer mechanisms which may lead to the identification of new therapeutic targets. ABSTRACT: Background: Cancer is the leading cause of disease-related mortality in children and malignancies are more frequently observed in individuals with primary immunodeficiencies (PIDs). This study aimed to identify and highlight the molecular mechanisms, such as oncogenesis and immune evasion, by which PID-related genes may lead to the development of pediatric cancers. Method: We implemented a novel bioinformatics framework using patient data from the TARGET database and performed a comparative transcriptome analysis of PID-related genes in pediatric cancers between normal and cancer tissues, gene ontology enrichment, and protein–protein interaction analyses, and determined the prognostic impacts of commonly mutated and differentially expressed PID-related genes. Results: From the Fulgent Genetics Comprehensive Primary Immunodeficiency panel of 472 PID-related genes, 89 genes were significantly differentially expressed between normal and cancer tissues, and 20 genes were mutated in two or more patients. Enrichment analysis highlighted many immune system processes as well as additional pathways in the mutated PID-related genes related to oncogenesis. Survival outcomes for patients with altered PID-related genes were significantly different for 75 of the 89 DEGs, often resulting in a poorer prognosis. Conclusions: Overall, multiple PID-related genes demonstrated the connection between PIDs and cancer development and should be studied further, with hopes of identifying new therapeutic targets.