TUMOR SUPPRESSOR GENES IN RENAL CELL CARCINOMA

人肾组织杂合性缺失及细胞遗传学分析 细胞癌(RCC)已被广泛应用于尝试 了解不同类型的RCC的演变。这种病有 已经被深入研究，因为它既有零星的发病，也有 以及罕见的家族遗传。结果是零星的和 家族性肾细胞癌已被明确阐明。3p等位基因丢失发生在 虽然3p上的精确区域在起源中很重要，但频率很高 癌症的病因尚未阐明。这种疾病的家族性形式 被认为涉及等位基因丢失的最近端区域，因为 与该基因相关的特定细胞遗传学易位的断裂点 疾病聚集期在3p13-14左右。然而，RCC的零星形式是 被认为涉及近端区域以及可能更多 包括3p21.3区域或最远端Von的远端遗传基因座 3p25的Hippel-Lindau病基因座。也有相当大的争论 关于肾细胞癌中3p缺失的细胞类型特异性。我们的 实验室已经开发出一种快速基因检测系统，使 3P区在抑制肾细胞癌中的功能分析 体内致瘤性。构建了定义的微细胞杂交克隆 在肾细胞癌细胞系中含有3P片段。这些混血儿展示了 体内肿瘤显著抑制，仅维持15-20Mb 人类染色体3p的片段，包含3p14-3q11区域。 此外，初步研究表明，肿瘤的机制 抑制包括体内细胞的快速死亡。在这项提案中，我们将 确定其中一个区域内的遗传基因座的参与情况 家族性肾癌与散发性肾癌(3p14-3q11)等位基因缺失最高 疾病的形式以及确定细胞类型的特异性 轨迹。对于这些实验，定义的微细胞杂交将是 其在RCC细胞中包含区域3p14-3q11 背景资料。该地区将被引入不同类型的 裸鼠体内杂交细胞生长检测肾癌及其致瘤性的研究 老鼠。这项研究的长远目标是孤立这部小说 高频区最近端的抑癌基因 肾癌的等位基因丢失及其作用机制的研究 重要的肿瘤抑制基因。

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.