CELL CYCLE REGULATORS AS TUMOR MARKERS IN BLADDER CANCER

描述：(申请人描述)我们的主要目标是 提案的重点是继续表征突变和 细胞周期调节因子的表达模式发生改变 与肿瘤的发生和发展过程有关 膀胱癌。我们的假设是分子异常 TP53和Rb基因，以及那些直接或间接 影响他们的编码产品，产生选择性优势 膀胱癌的肿瘤生长与侵袭性行为 病人。这得到了以下事实的支持：TP53突变和 P53和pRb蛋白表达异常是膀胱癌的常见事件 肿瘤，并与不良的临床结果和减少 病人存活率。最近，9p21处的缺失影响了pl6和pl5， 已被证明发生在膀胱癌中，并与 有浅表的损伤。此外，某些细胞周期和细胞周期蛋白- 依赖的激酶已被证明成为激活的癌基因 癌症的一个子集。对这些更改的识别可以 进而揭示它们作为肿瘤标记物的重要临床价值。 膀胱炎患者的早期发现和监测 癌症，以及在预测肿瘤行为方面。我们的目标是 计划是将基础研究成果转化为临床研究， 并与网络实验室和NCI合作 世界卫生组织推荐的肿瘤标志物评价中的代表 协调委员会。具体目标概述如下： 目的#1：Tp53和Rb的分子和功能分析 浅表性和浸润性膀胱癌。我们计划前瞻性地 验证我们实验室和其他小组之前的报告 提示TP53和Rb对预后的预测价值。我们还将学习-- 其通路的流事件，包括MDM2和E2F蛋白。 此外，将进行P53和pRb的功能研究，以 将沉默的突变与那些导致 恶性表型。 目的#2：细胞周期蛋白依赖性激酶抑制(CKI)的特性 膀胱癌的基因突变。由于这一点的隐性性质 新的负调控者家族，有人建议他们 起到抑制基因的作用。来自我们小组和其他人的报道 研究人员发现，某些CKI基因(主要是pl6和pl5) 在膀胱癌中发生突变。我们建议确定他们的 在膀胱肿瘤中，失活是一种早期和常见的事件。 此外，我们将测试重新引入野生型基因是否可以 逆转膀胱癌细胞的致瘤表型。目标明确 这些基因的破坏将进一步揭示它们在 发展和肿瘤发生。 目的#3：细胞周期蛋白和细胞周期蛋白的免疫表型和分子研究 膀胱癌中的依赖激酶。我们已经组装了一口井 针对特定细胞周期蛋白和细胞周期蛋白依赖性蛋白依赖性蛋白激酶的特化探针面板和计划 以确定异常表达模式的检测是否 临床病理后果，表明他们的 鉴别是有预后价值的。

DESCRIPTION: (Applicant's Description) The main objective of our proposal focuses on the continued characterization of mutations and altered patterns of expression of cell cycle regulators as they relate to processes of tumorigenesis and tumor progression in bladder cancer. It is our hypothesis that molecular abnormalities of TP53 and RB genes, as well as those that directly or indirectly affect their encoded products, produce a selective advantage for tumor growth and an aggressive behavior in bladder cancer patients. This is supported by the facts that TP53 mutations and altered expression of p53 and pRB are frequent events in bladder tumors and are associated with poor clinical outcome and reduced patient survival. Recently, deletions at 9p2l, affecting pl6 and pl5, have been documented to occur in bladder tumors and were associated with superficial lesions. In addition, certain cyclins and cyclin- dependent kinases have been shown to become activated oncogenes in a subset of cancers. Identification of these alterations may in turn reveal their important clinical value as tumor markers for the early detection and monitoring of patients affected with bladder cancer, as well as in predicting tumor behavior. The goals of our program are to translate basic research findings into clinical studies, and to collaborate with the Network laboratories and NCI representatives in the evaluation of tumor markers recommended by the Coordinating Committee. The Specific Aims are outlined as follows: Aim #1: Molecular and Functional Analyses of TP53 and RB in Superficial and Invasive Bladder Cancer. We plan to prospectively validate previous reports from our laboratory and other groups that showed the prognostic value of TP53 and RB. We will also study down- stream events of their pathways, including mdm2 and E2F proteins. Furthermore, functional studies of p53 and pRB will be conducted to distinguish silent mutations from those contributing to the malignant phenotype. Aim #2: Characterization of Cyclin-Dependent Kinase Inhibitory (CKI) Gene Mutations in Bladder Cancer. Due to the recessive nature of this new family of negative regulators, it has been suggested that they function as suppressor genes. Reports from our group and other coinvestigators revealed that certain CKI genes (mainly pl6 and pl5) are mutated in bladder tumors. We propose to determine if their inactivation is an early and frequent event in bladder tumors. Furthermore, we will test if reintroduction of wild type genes can revert the tumorigenic phenotype of bladder cancer cells. Targeted disruption of these genes will further disclose their role in development and tumorigenesis. Aim #3: Immunophenotypic and Molecular Studies of Cyclins and Cyclin- Dependent Kinases in Bladder Cancer. We have assembled a well characterized panel of probes to specific cyclins and Cdks and plan to determine if detection of abnormal patterns of expression are of clinicopathological consequences, suggesting that their identification is of prognostic value.