Genome-wide association study (GWAS) approaches to cancer have been successful at identifying novel susceptibility loci, but there remains a fundamental gap in understanding the biological and clinical relevance of these discoveries. This problem is especially acute as there is an urgent need to translate basic scientific advancements into clinically relevant deliverables that will impact cancer patient care. The long-term goal of this research proposal is to discover the heritable component of neuroblastoma, an important childhood cancer that continues to result in significant morbidity and mortality, and to use this knowledge to develop novel therapeutic strategies. The primary objective of this competitive renewal application, based on the published and unpublished results from the first 4 years of funding, is to discover how host genetic architecture explains neuroblastoma susceptibility and patient survival, while also extending our initial findings that genes uncovered by our GWAS play a central role in tumor progression and maintenance. The central hypothesis to be explored here is that heritable DNA variation influences the initiation of neuroblastoma, the clinical course of the disease, and patient outcomes. This hypothesis builds on our identification of multiple common and rare DNA variations associated with neuroblastoma, the observation that many of the genes identified through these efforts impart oncogenic dependencies in established tumors, and the fact that recurrent somatic mutations are exceeding rare, even in the most aggressive subsets of this disease. The motivation for the proposed research is the urgent need to improve high-risk neuroblastoma survival rates and decrease treatment-related morbidities. We will test our central hypothesis in three specific aims: 1) Discover common and rare DNA variants that are associated with neuroblastoma; 2) Identify the DNA polymorphisms that predict neuroblastoma patient survival; and 3) Determine how genes identified by the neuroblastoma GWAS act as oncogenic drivers of the malignant phenotype. The first Aim will continue our discovery efforts by increasing the resolution of the scan and doubling the number of cases and controls, with the goal of delivering the identifiable heritable component of neuroblastoma. Aim 2 is devoted to a GWAS within the neuroblastoma cases to define genetic determinants of patient survival, and this will build on our preliminary data identifying potential tumor cell intrinsic mechanisms of chemotherapy resistance via this approach. The final Aim will determine the mechanism by which genes identified by the most robust association signals act as tumor suppressors or oncogenes in neuroblastoma cells, again building on our extensive preliminary data. We consider this project significant because it will define DNA variation, genes and pathways critical to neuroblastoma initiation and progression, and thus provide insights that will be actionable in the clinic and ultimately result in improved cure rates.