Loss of heterozygosity as well as cytogenetic analyses of human renal cell carcinoma (RCC) have been utilized extensively in an attempt to understand the evolution of the different types of RCC. This disease has been intensely studied because it occurs both with sporadic incidence as well as with rare familial inheritance. The result in sporadic and familial RCC have been clearly elucidated. Loss of 3p alleles occurs at high frequency although the exact region on 3p important in the genesis of the cancer has not been elucidated. The familial form of the disease is thought to involve the most proximal region of allele loss since the breakpoint in specific cytogenetic translocations associated with the disease cluster around 3p13-14. However, the sporadic form of RCC is considered to involve the proximal region as well as potentially more distal genetic loci including the region 3p21.3 or the most distal Von Hippel-Lindau disease locus at 3p25. There is also considerable debate with regard to the cell-type specificity of 3p losses in RCC. Our laboratory has developed a rapid genetic assay system that has allowed functional analysis of a defined region of 3p in the suppression of RCC tumorigenicity in vivo. Defined microcell hybrid clones were constructed containing a fragment of 3p in an RCC cell line. These hybrids showed a dramatic tumor suppression in vivo and maintained only a 15-20 Mb fragment of human chromosome 3p encompassing the region 3p14-3q11. Furthermore, preliminary studies indicate that the mechanism of tumor suppression involves rapid cell death in vivo. In this proposal, we will determine the involvement of genetic loci within one of the regions of highest allele loss in RCC (3p14-3q11) in the familial versus sporadic form of the disease as well as to determine the cell-type specificity of the locus. For these experiments defined microcell hybrids will be constructed which contain the region 3p14-3q11 in the RCC cell background. This region will be introduced into the different types of RCC and tumorigenicity assayed by growth of hybrid cells in athymic nude mice. It is the long range goal of this research to isolate the novel tumor suppressor gene within the most proximal region of high frequency allele loss in RCC and determine the mechanism of action of this important tumor suppressor gene.
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