Genetic Risk Profiling in Metastatic Prostate Carcinoma

描述（由申请人提供）：PSA筛查有助于前列腺癌诊断病例数量的急剧增加和这种疾病死亡率的微妙下降。不幸的是，许多患者仍然患有侵袭性的、潜在致命的疾病，这是因为1）患者没有参加筛查计划，2）该计划没有足够早地发现疾病以治愈或3）所选择的治疗没有根除疾病。与此同时，许多男性经历了多年不必要的筛查和/或被诊断患有低转移潜力的前列腺癌。我们需要的是识别男性的标志物，这些男性不是处于患前列腺癌的高风险中，而是处于死于前列腺癌的高风险中。在发生疾病之前识别高风险男性将允许密集的筛查和/或预防，同时保留那些处于低风险年的筛查。在诊断后识别高风险男性将允许靶向治疗，同时保留那些低风险的潜在病态治疗。我们相信，分析常见的多态性变异将允许这种风险分层。本申请的目的是鉴定哪些DNA多态性与转移性前列腺癌的风险相关，因此是侵袭性前列腺癌的潜在标志物。我们建议进行一项病例对照研究，以确定与晚期前列腺癌相关的多态性变异，使用转移性前列腺癌患者作为我们的病例，很少或没有发生前列腺癌风险的个体作为我们的对照。这项建议有两个具体目标。(I)目的建立晚期前列腺癌患者和正常人的体细胞DNA库。（II）探讨基因型与晚期前列腺癌的关系。研究转移性疾病患者的基本原理有两个方面。首先，转移性疾病患者明确具有临床重要的前列腺癌。因此，没有患者的惰性疾病，以掩盖显着的关联。第二，由于这些患者的早期识别有可能产生最大的影响，他们是应该进行研究的患者。在这项研究结束时，我们将有一组标志物，在未来的前瞻性研究中，这些标志物有可能预测哪些患者最终死于前列腺癌的高风险。

DESCRIPTION (provided by applicant): PSA screening has contributed to a dramatic increase in the number of prostate cancer cases diagnosed and a subtle decrease in mortality from this disease. Unfortunately, many patients still present with aggressive, potentially lethal disease either because 1) the patient did not participate in a screening program, 2) the program did not identify the disease early enough for cure or 3) the treatment chosen did not eradicate the disease. At the same time, many men go through years of unnecessary screening and/or are diagnosed with prostate carcinoma with low metastatic potential. What is needed are markers to identify men, not at high risk of having prostate carcinoma, but at high risk of dying of prostate carcinoma. Identification of high risk men prior to developing the disease would allow intense screening and/or prophylaxis while sparing those at low risk years of screening. Identification of high risk men after diagnoses would allow targeted therapy while sparing those at low risk potentially morbid treatment. We believe that analysis of common polymorphic variants will allow exactly this risk stratification. The objective of this application is to identify which DNA polymorphisms that are associated with risk for metastatic prostate carcinoma and therefore are potential markers for aggressive prostate cancer. We propose to perform a case-control study to identify polymorphic variants associated with advanced prostate cancer using patients with metastatic prostate carcinoma as our cases and individuals with little or no risk of ever developing prostate carcinoma as our controls. There are two specific aims to this proposal. (I) To establish a bank of somatic DNAs from advanced prostate cancer patients and race matched controls. (II)To search for associations between genotypes and risk of advanced prostate carcinoma. The rationale for studying patients with metastatic disease is two fold. First, patients with metastatic disease unequivocally have clinically important prostate carcinoma. As a result, there are no patients with indolent disease to obscure significant associations. Second, since these are the patients in whom earlier identification has the potential to make the greatest impact, they are the patients who should be studied. At the conclusion of this study, we will have a panel of markers with the potential to predict, in future prospective studies, which patients are at high risk of eventual death from prostate carcinoma.