LAUSR

Pediatric neuroblastoma is among the most common solid tumors in children and accounts for approximately 15% of childhood cancer mortalities. Neuroblastomas are highly heterogeneous cancers, and few common genetic alterations are currently associated with neuroblastoma tumorigenesis. Additionally, few genetic variations have been established as predictive factors for clinical outcomes in neuroblastoma cases. Here, a biological systems-level approach utilizing publicly-accessible data from the Genomic Data Commons was taken to identify genetic variations associated with altered survival times in neuroblastoma cases. Two survival analyses of clinical neuroblastoma cases were conducted: one associated with genetic variations in individual somatic genes and the other associated with groups of mutations identified using functional enrichment analysis. Mutations in only two individual genes displayed significant associations with altered survival: ALK (ALK receptor tyrosine kinase), a known hallmark of neuroblastoma, and DNAH17 (dynein axonemal heavy chain 17). In contrast, patient cohorts established by functional enrichment analysis of mutated genes identified 148 biological systems where somatic gene variations were significantly associated with altered survival. Gene sets defined by the function of their products in ALK signaling, as well as alteration in cells treated with Crizotinib, an inhibitor of receptor tyrosine kinases including ALK, both displayed highly significant association with altered survival. Of the 148 systems identified, 128 others lacked any association with ALK. Of these, eight showed a more significant association with altered survival than the ALK signaling pathway itself. These results identify novel risk factors associated with reduced survival in pediatric neuroblastoma patients and illustrate the potential of systems-level analysis to generate insight into the biology of heterogeneous cancers. Citation Format: Nolan D. Middleton, Eric Shelden. Functional enrichment analysis of somatic mutations identifies novel risk factors for pediatric neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 882.