Heritable factors are an important determinant of cancer risk. At present, only a small fraction of this genetic risk is explained by known cancer predisposition genes. Our preliminary data suggests that in pediatric cancers or cancers that occur in early adulthood, de novo or "new" genetic mutations may be identified that contribute to cancer causation. As such, the aim of our study is to study children with specific types of cancer (leukemia and neuroblastoma) without a family history of the disease to determine if we can identify the genetic cause of their cancer. Based upon a unique ascertainment of DNA samples from case-parent trios (unaffected parents and cancer affected child), this proposal will use next-generation sequencing approaches to detect de novo germline mutations that may account for cancer susceptibility in these young patients. This approach represents a new paradigm in cancer genetics, which could have broad applications in terms of cancer risk stratification and the primary prevention of hereditary cancers in the growing number of survivors of these childhood malignancies.