Neuroblastoma remains one of the deadliest cancers in children. Understanding the genetic differences between low- and high-risk neuroblastomas is critical to improving our prognostic abilities and to providing therapeutic targets. Most invasive neuroblastomas are defined either by MYCN amplification (40%) or 11q loss of heterozygosity (30%), but rarely do these occur in the same tumor. The clinical significance of 11q loss strongly suggests that one or more neuroblastoma tumor suppressor genes are located in this region. Notably, there have been no bona fide neuroblastoma suppressor genes discovered. We hypothesize that functional inactivation of at least two genes located at 11q is required for the development of an aggressive neuroblastoma phenotype in the absence of oncogenic activation of MYCN. This proposal seeks to discover 11q neuroblastoma suppressor genes by achieving the following specific aims: (1) identify 11q regions associated with aggressive neuroblastoma;(2) identify relevant 11q genes using functional and genetic approaches;and (3) confirm the biological relevance of candidate 11q tumor suppressor genes. Chromosome arm 11q aberrations are also present in many other human cancers, suggesting that any 11q neuroblastoma suppressor gene might also be involved in the pathogenesis of other malignancies. This proposal lays out a 5-year research and training program with the ultimate goal to transition the principal investigator to an independent R01-funded physician-scientist. His mentors and advisors are leaders in the field of neuroblastoma research and cancer genetics. He will take advantage of the ample resources of his environment, both at the Children's Hospital of Philadelphia and the University of Pennsylvania. Relevance: Increases in treatment intensity in neuroblastoma have resulted in only modest improvements in survival;it is clear that new approaches are needed. We propose a systematic approach to discovering tumor suppressor genes on chromosome arm 11q, which is often deleted in aggressive neuroblastoma. This will directly impact the treatment of children with neuroblastoma by improving our prognostic ability and providing new avenues for drug development.