TUMOR SUPPRESSOR GENES IN RENAL CELL CARCINOMA

人肾细胞癌基因杂合性丢失及细胞遗传学分析 细胞癌（RCC）已被广泛用于试图 了解不同类型RCC的演变。 这种疾病 被深入研究，因为它既有零星的发病率， 以及罕见的家族遗传。 结果是零星的， 家族性肾细胞癌已被清楚阐明。 3 p等位基因的缺失发生在 虽然3 p上的确切区域在起源中很重要， 癌症的病因尚未阐明。 这种疾病的家族形式 被认为涉及等位基因丢失的最近端区域， 在特定的细胞遗传学易位断点与 疾病聚集在3 p13 -14附近。 然而，RCC的散发形式是 被认为涉及近端区域以及潜在的更多 包括3p21.3区域或最远端Von Hippel-Lindau病基因座位于3 p25。 也有相当多的争论 关于RCC中3 p丢失的细胞类型特异性。 我们 一个实验室开发了一种快速基因检测系统， 3 p特定区域在肾细胞癌抑制中的功能分析 体内致瘤性。 构建了确定的微细胞杂交克隆 在RCC细胞系中含有3 p的片段。 这些混血儿表现出 在体内显著的肿瘤抑制，仅维持15-20 Mb 人类染色体3 p的片段，包括3 p14 - 3q 11区域。 此外，初步研究表明，肿瘤的机制， 抑制涉及体内快速细胞死亡。 在本提案中，我们将 确定一个区域内的遗传位点的参与， 在家族性与散发性肾细胞癌（3 p14 - 3q 11）中， 疾病的形式以及确定细胞类型特异性 轨迹 对于这些实验，定义的微单元混合体将被 构建了包含RCC细胞中3 p14 - 3q 11区域的 背景 该区域将被引入不同类型的 肾细胞癌及其杂交细胞裸鼠移植瘤的研究 小鼠 本研究的长期目标是将小说中的 肿瘤抑制基因在最近端区域内的高频表达 在RCC等位基因丢失，并确定其作用机制， 重要肿瘤抑制基因。

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.