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。尽管不到10%的 膀胱癌有激活的ras基因，就像在小鼠身上证明的那样。 3t3检测，我们发现在所有高级别膀胱癌中ras p21均升高。 癌症检查。在建议的研究中，我们会把 P21的免疫组织化学分析在一大批慢性粒细胞白血病患者中的表达 “癌前病变”和肿瘤性膀胱病变，我们对它们有广泛的了解 临床随访。在这些研究中，我们将尝试确认 我们在其中定义了p21表达模式的初步工作 正常尿路上皮及p21表达与非典型性程度的关系 癌组织中的异常增生性病变和组织学分级。我们将决定 浸润性膀胱癌p21的组织发生处于什么阶段 表达增加，如果复发和转移的肿瘤进展为 高表达p21的肿瘤细胞群。特别的 重要的是研究p21表达与肿瘤分级的相关性， 分期和临床转归。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 明显不典型增生和低级别的那一组患者 高风险的乳头状癌最终发展为 浸润性癌。此外，我们将检测尿液细胞中的p21以 确定该化验方法是否可作为常规尿液细胞学检查的有效辅助手段 在尿道癌的诊断中。 在对膀胱癌标本的生化研究中，我们将确定一种 特定的ras基因持续表达，并进行定量和 对该特定RAS稳态mRNA水平的定性分析 吉恩。我们将确定p21分子是正常的还是改变的 通过分析蛋白在膀胱肿瘤中的电泳迁移率 肿瘤p21及肿瘤DNA中ras基因氨基酸突变分析 位置12和61。此外，我们将确定是否增加了表达 Ras p21的表达与ras基因扩增或结构改变有关。 有问题的ras基因的改变。 因此，在这些研究中，我们将确定ras p21是否与 肿瘤标志物在膀胱癌检测和预后中的作用 确定ras基因在本病中激活的具体机制 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.