Wilms' tumor of the kidney is one of the most common pediatric cancers and is a leading cause of cancer mortality in children worldwide. Wilms' tumor occurs in both familial and sporadic forms and is believed to arise from persistent metanephric blastema resulting from a failure of differentiation. The WT1 gene was identified more than 10 years ago and, despite the efforts of several laboratories, remains the only tumor suppressor gene known to be involved in Wilms' tumor. However, WT1 is involved in less than 10% of cases suggesting that other genes must be involved. The analysis of chromosome rearrangement breakpoints, particularly translocations, has been extremely successful in the discovery of novel genes involved in cancer. The goals of the studies proposed in this application are to identify the gene or genes affected by an apparently balanced constitutional t(5;6)(q21;q21) identified in a patient with bilateral Wilms' tumor and to test these genes for involvement in our panel of Wilms' tumors. The 6q21 region is involved in three other reported cases of translocations associated with Wilms' tumor and most likely harbors the relevant gene(s). The two derivative chromosomes resulting from this rearrangement have been segregated into somatic cell hybrids which provide powerful reagents to precisely localize the breakpoint regions on chromosome 5 and 6.
The specific aims of this proposal are: 1. Precisely locate rearrangement breakpoints of the t(5;6)(q21;q21) in a patient with bilateral Wilms' tumor. 2. Identify the gene(s) disrupted by the Wilms' tumor associated t(5;6)(q21;q21). 3. Analyze our collection of Wilms' tumors for mutations, rearrangements, promoter methylation and altered expression of genes identified in Specific Aim 2. The identification of novel genes that contribute to the etiology of Wilms' tumor will help elucidate the mechanisms by which differentiating kidney cells become transformed during development. Furthermore, the characterization of these genes may provide novel opportunities for diagnosis and treatment of this cancer.
