Neuroblastoma is the most common solid tumor of early childhood and the most common cancer of any type diagnosed during infancy. Despite an aggressive approach for the treatment of high-risk patients (50% of all cases), most of these children still die of their disease. The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of tumor progression varying widely. The molecular pathways leading to the development of neuroblastoma are complex and may explain the observed clinical heterogeneity. Invasive and metastatic neuroblastomas show consistent rearrangements and can be subdivided into two major subsets: 1p deletion and high-level amplification of the MYCN oncogene in the most aggressive subset (40% of high-risk cases), and unbalanced loss of 11q material and 3p LOH with MYCN single-copy in the other. We hypothesize that in the absence of oncogene amplification, coordinate inactivation of at least two tumor suppressor genes located at 3p and 11q is required to develop a high-risk neuroblastoma phenotype. This proposal seeks to achieve the following aims: 1) Identify and map 3p and 11q deletions in a representative set of primary neuroblastoma tumors using high-resolution array-based comparative genomic hybridization (aCGH);2) determine the influence 3p and 11q deletions have on region-specific gene expression, clinical phenotype and patient outcome;and 3) combine structural and functional approaches for the identification of a 3p neuroblastoma suppressor gene(s). Correlating aCGH and expression profiling data on a carefully annotated set of representative human neuroblastoma tumors will allow us to prioritize the most promising putative neuroblastoma suppressor genes whose alteration is required for a high-risk phenotype, and ultimately exploiting them as therapeutic targets for this often lethal childhood cancer. This proposal describes a 5 year training program that is ambitious, yet feasible. It is designed to allow the candidate to develop the skills and experience required of an independent physician-scientist. The principal investigator will be mentored by leaders in the field of pediatric neuroblastoma research and cancer genomics at both the Children's Hospital of Philadelphia and the University of Pennsylvania. Such an environment will maximize the potential for the principal investigator to establish a scientific niche from which an academic career can be constructed. Successful completion of this project will have an immediate impact on pediatric oncology, but the methodology and data acquired will also likely be relevant to cancer biology in general.
| Mosse, Yael P; Laudenslager, Marci; Longo, Luca et al. (2008) Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455:930-5 |
| Mosse, Yael P; Diskin, Sharon J; Wasserman, Nora et al. (2007) Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression. Genes Chromosomes Cancer 46:936-49 |
