Modes of Prostate Ca Progression--role of p53 Pathway

描述：(改编自调查人员摘要)过去十年 转移性前列腺癌导致40多万美国男性死亡，今天 仍然是20001年度美国男性癌症死亡的第二大常见原因。这个 前列腺癌转移的分子基础还知之甚少。 对直接来源于人转移性前列腺癌细胞的研究很少 患有这种疾病的病人。此外，分子基础的增加 非裔美国人前列腺癌的发病率和预后较差 不确定。我们假设上游和下游效应器的变化 P53基因的功能和P53基因本身是重要的贡献者 前列腺癌的进展。这一假设将通过以下两个方面进行检验 特定目标：特定目标1将检查P53途径的关键成员 (p53、Cavelin-L、p14、p21、mdm2和ATM)。 雄激素依赖和雄激素非依赖性骨、淋巴和内脏 81例患者的转移灶。分子分析技术的组合 将决定1)P53途径改变的统一模式是否发生在 来自单个患者的多个转移部位的样本以及2)是否 特定的变更模式与特定的 前列腺癌的扩散(例如，单纯骨癌与骨加内脏癌 站点)。已确定的信息量最大的分子技术将用于 检查最初前列腺癌时切除的前列腺癌组织 从81名患者中的30名患者中进行诊断，以提供洞察 这条途径改变的时间。其他分析将比较 基因组杂交数据与P53途径数据的平行比较 用于识别与特定缺陷相关的得失的样本 在P53途径中。《特定目标2》将根据最近的数据对这一假设进行检验 已发表数据2‘3，P53改变模式的变化 途径可能是前列腺癌侵袭性增加的原因 非裔美国人。结果来自31个雄激素依赖和 非裔美国人的雄激素非依赖性转移性前列腺癌 与这项分析中50名白人和西班牙裔患者的样本进行了比较。这个 这些研究的结果将对未来的选择产生直接影响 为前列腺癌患者提供的基因治疗和其他治疗方法，2) 将有助于评估肿瘤模型的相关性，在这些模型中，p53失活是一种 关键因素，以及3)将有助于识别所需的基因组数据元素 定义前列腺癌表型。

DESCRIPTION: (Adapted from the investigator's abstract) In the past ten years metastatic prostate cancer killed more than 400,000 American men and today remains the second most common cause of cancer death in U.S. men in 20001. The molecular basis of prostate cancer metastasis is poorly understood and has been rarely studied in human metastatic prostate cancer cells derived directly from patients with this disease. Moreover, the molecular basis for the increased incidence and poorer prognosis for prostate cancer in African-Americans remains uncertain. We hypothesize that alterations of upstream and downstream effectors of p53 gene function, and of the p53 gene itself, are important contributors to prostate cancer progression. This hypothesis will be tested through two specific aims: Specific Aim 1 will examine critical members of the p53 pathway (p53, Caveolin-l, p14, p21, MDM2, and ATM) in a series of 143 androgen-dependent and androgen-independent bone, lymph node, and visceral metastases from 81 patients. A combination of molecular analysis techniques will determine 1) whether uniform patterns of p53 pathway alteration occur in samples from multiple metastatic sites from individual patients and 2) whether specific patterns of alteration are associated with specific modes of dissemination of prostate cancer (e.g., bone only versus bone plus visceral sites). The most informative molecular techniques identified will be used to examine prostate cancer tissue removed at the time of initial prostate cancer diagnosis from a subset of 30 of the 81 total patients to provide insight into the timing of alteration of this pathway. Additional analysis will compare comparative genomic hybridization data to the p53 pathway data in parallel specimens to identify gains or losses that are associated with specific defects in the p53 pathway. Specific Aim 2 will test the hypothesis, based on recently published data2'3, that variations in the pattern of alteration of the p53 pathway may account for increased aggressiveness of prostate cancer in African-Americans. Results from a subset of 31 androgen-dependent and androgen-independent metastatic prostate cancers from African-Americans will be compared to samples from 50 White and Hispanic patients in this analysis. The results of these studies will 1) have a direct impact on future selection of gene therapy and other therapies offered to patients with prostate cancer, 2) will help evaluate the relevance of tumor models in which p53 inactivation is a critical factor, and 3) will help identify genomic data elements needed to define prostate cancer phenotypes.