ONCOGENE EXPRESSION IN HUMAN BLADDER CANCER

在人类实体瘤中发现的主要转化诱导基因是 细胞癌基因ras家族的成员。 虽然只有不到10%的 膀胱癌具有激活的ras基因，如在小鼠中所证实的， 3T3检测，我们发现所有高级别膀胱癌中ras p21均升高， 检查癌细胞。 在拟议的研究中，我们将扩大 p21蛋白免疫组化分析在一个大的肺癌患者队列中的应用 “癌前”和肿瘤性膀胱病变，我们有广泛的 临床随访。 在这些研究中，我们将试图证实 初步工作中，我们确定了p21的表达模式，发现在 p21蛋白表达与尿失禁程度的相关性 癌的异型增生病变和组织学分级。 我们将决定 p21在浸润性膀胱癌组织发生的哪个阶段 表达增加，如果复发肿瘤和转移发展为恶性肿瘤， 表达高水平p21的肿瘤细胞群。 特别 重要的是将p21表达与肿瘤分级相关联的研究， 阶段和临床结果。 使用p21表达作为表型标记 对于尿路上皮细胞的恶性潜能，我们将尝试识别 该亚组的患者有明显的发育不良和低级别的 乳头状癌是高风险的最终发展， 浸润性癌 此外，我们将检测尿细胞中的p21， 确定该检测是否是常规尿细胞学检查的有用辅助手段 泌尿系统癌症的诊断。 在膀胱癌标本的生化研究中，我们将确定 特异性ras基因持续表达并进行定量， 特定ras稳态mRNA水平的定性分析 基因 我们将确定是否正常或改变p21分子， 通过分析电泳迁移率在膀胱肿瘤中表达 肿瘤p21和通过分析肿瘤DNA中ras基因氨基酸突变 位置12和61。 此外，我们将确定是否增加表达 rasp21的表达与ras基因扩增或结构性 ras基因的改变。 因此，在这些研究中，我们将确定ras p21是否是一个相关的 肿瘤标志物在膀胱癌的检测和预后中的作用， 确定ras基因激活的具体机制， 人类癌症

The major transformation-inducing genes found in human solid tumors are members of the ras family of cellular oncogenes. Although less than 10% of bladder carcinomas have activated ras genes, as demonstrated in the mouse 3T3 assay, we have found elevated ras p21 in all high-grade bladder carcinomas examined. In the proposed studies we shall extend the immunohistochemical analysis of p21 to a large cohort of patients with "precancerous" and neoplastic bladder lesions, on whom we have extensive clinical follow-up. In these sudies we shall attempt to confirm preliminary work in which we define the pattern of p21 expression found in normal urothelium and correlated p21 expression with degree of atypia in dysplastic lesion and histologic grade in carcinomas. We shall determine at what stage in the histogenesis of invasive bladder carcinoma p21 expression is increased and if recurrent tumors and metastases evolve a population of tumor cells which express high levels of p21. Of particular importance will be studies correlating p21 expression with tumor grade, stage and clinical outcome. Using p21 expression as a phenotypic marker for malignant potential of urothelial cells, we shall attempt to identify that subgroup of patients with marked dysplasia and with low grade papillary carcinomas who are at high risk for the ultimate development of invasive carcinoma. Further, we shall assay p21 in urine cells to determine if this assay is a useful adjunct to conventional urine cytology in the diagnosis of urinary tract cancer. In biochemical studies of bladder cancer specimens, we shall determine if a specific ras gene is consistently expressed and perform quantitative and qualitative analysis of steady state mRNA levels for that specific ras gene. We shall determine whether a normal or altered p21 molecule is expressed in bladder tumors by analysis of the electrophoretic mobility of tumor p21 and by analysis of tumor DNA for ras gene mutations at amino acid positions 12 and 61. Further, we shall determine if increased expression of ras p21 is associated with ras gene amplification or a structural alteration of the ras gene in question. Therefore, in these studies we shall determine if ras p21 is a relevant tumor marker in the detection and prognosis of bladder cancer, as well as determining the specific mechanism of ras gene activation in this common human cancer.