Germline Functional Variants Contribute to Somatic Mutation and Outcomes in Neuroblastoma

Abstract Germline genetic context may play a significant role in the development and evolution of cancer, particularly in childhood cancers such as neuroblastoma. We studied the role of putatively functional germline variants (pFGVs) in neuroblastoma, even if they do not directly increase disease risk. Our whole-exome sequencing analysis of 125 patients with neuroblastoma revealed a positive correlation between pFGV burden and somatic mutations. Moreover, patients with higher pFGV burdens exhibited worse outcomes. Similar findings were observed in the separate neuroblastoma cohort. However, contrasting results emerged in adult-onset cancer, emphasizing the importance of germline genetics in neuroblastoma. The enrichment of pFGVs in cancer predisposition genes was evident in neuroblastoma compared to that in healthy and adult-onset cancer populations, and their presence had prognostic significance in neuroblastoma. The combination of germline and clinical risk factors improves survival predictions. Our study highlights the importance of germline variants and their potential implications in pediatric cancer.