| Wilms tumor is the most common form of childhood renal tumor with an estimated incidence of 1 in 10 000 live births. Overall survival is good, exceeding 85% with current therapies; however, a subset of children are resistant to treatment and eventually succumb to their disease. Only one gene, WT1, has been cloned and proven to be involved in the etiology of Wilms tumor. However, defects in this gene account for only approximately 10--20% of sporadic Wilms tumors indicating that Wilms tumors are genetically heterogeneous. Identification of genes involved in the initiation or and/or progression of Wilms tumor is needed in order to gain a better understanding of this cancer and aid in the development of prognostic factors and refinement of current therapies. Therefore, our global objective was to identify and characterize candidate Wilms tumor genes using a combination of methodologies.;The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth syndrome in which individuals are predisposed to the development of Wilms tumor. Defects in the gene, GPC3, give rise to SGBS. Therefore, we hypothesized that some tumors from non-SGBS individuals may harbor GPC3 mutations. We conducted an extensive mutation analysis of the GPC3 gene in 64 Wilms tumors. However, it was found that defects in the GPC3 gene in non-syndrome-associated Wilms tumors were not a common occurrence.;Approximately 20% of Wilms tumors lose heterozygosity of chromosome 16q and this loss is associated with poor prognosis. We therefore proposed to identify Wilms tumor gene(s) on chromosome 16q and/or its downstream targets utilizing differential display PCR and an in silico approach of database searching. Ksp-cadherin was identified in silico as a strong Wilms tumor candidate gene and was further evaluated in 34 Wilms tumors. Interestingly, Ksp-cadherin RNA and protein was found to be expressed in all fetal and mature kidney tested but was absent in the majority of Wilms tumors evaluated. These results suggest that loss of Ksp-cadherin expression may be involved in the pathogenesis of Wilms tumor and warrants further evaluation. |
