Abstract: Wilms tumor represents the most common renal neoplasm of childhood. Remarkable success has been achieved in the therapy of WT through the National Wilms Tumor Study Group (NWTS). Despite the responsiveness of most WT to adjuvant chemotherapy, some tumors are unresponsive and result in tumor progression and death. Most tumors lack distinctive histologic or clinical features to targeting with more or less aggressive chemotherapy. Recognizing biologically distinctive subsets of WT may be useful for predicting clinical behavior and targeting therapy. The goal of this project is to identify molecular categories of WT that have predictable clinical properties, including propensity to metastasize and response to therapy. We hypothesize that gene expression profiles will aid in the recognition of these categories. AIM ONE: To identify candidate marker genes that are differentially expressed: Using commercially available cDNA macro-arrays, we will comprehensively analyze gene expression in a small group of Wilms tumors. A subset of genes whose expression varies throughout these tumors will be identified. AIM TWO: To identify molecular categories of Wilms tumor based upon the expression of candidate marker genes identified in Aim One: Utilizing custom cDNA microarrays approximately 200-300 pathologically, clinically and genetically characterized WT will be analyzed. Using computationally assisted methods, profiles of gene expression that define molecular categories of Wilms tumors will be identified.
AIM THREE: To verify, test, and model the new molecular categories of Wilms tumor and to examine these new categories in their clinical, pathologic, and genetic context. Each molecular category will be analyzed and validated for clinical, pathologic and genetic features using the extensive resources of the NWTS. Genes predictive of molecular categories will be verified using in situ hybridization or immunohistochemistry. A model categorization will be proposed and tested on 200 additional Wilms tumors.