Wilms' tumor (WT) is the most common primary malignant solid tumor of childhood, accounts for 6-7% of all childhood malignancies in the United States, and is an important model for the study of the fundamental mechanisms of tumorigenesis. The WT1 gene was identified and positionally cloned in 1991, but we have shown that this gene is only involved in a very small percentage (-5-7%) of WT patients. Since the cloning of WT1, no additional genes have been shown to be directly involved in the development of WT. Several groups, including our own, have attempted to identify new regions associated with WT through genome wide LOH (Loss of Heterozygosity) analysis and CGH (Comparative Genomic Hybridization) analysis on metaphase chromosomes, resulting in the association of chromosomes 5q (22%) 7p (15%) and 16q (12%) with WT. While these studies have provided some evidence for genomic regions harboring genes involved in Wilms' tumorigenesis, no gene has yet been cloned to coincide with these regions. These efforts have been hampered by the lack of robust, high throughput, high resolution techniques for detecting submicroscopic deletions and amplifications. Thus, the genetic defect(s) in the majority of these patients still remains unclear. It is clear that WT results from abrogation of the normal developmental pathways within the kidney. Identification of additional genes involved in WT pathogenesis will not only advance our understanding of Wilms' tumorigenesis, but also uncover crucial events required for proper cellular differentiation and normal kidney development. We have been developing a high throughput array based technology that will allow us to scan the genome for deletions and amplifications, or copy number aberrations (CNAs), at 0.5-1mb level of resolution. Hybridization of tumor DNA to these arrays readily identifies losses and gains in the tumor samples using a normal DNA reference. We will identify the recurrent copy number aberrations present in our WT bank, tile the implicated chromosomal regions on WT subarrays, and identify candidate genes involved in WT and kidney development.
