Genetic Risk Profiling in Metastatic Prostate Carcinoma

描述(由申请人提供)：PSA筛查有助于大幅增加前列腺癌的确诊病例数量，并略微降低这种疾病的死亡率。不幸的是，许多患者仍然患有侵袭性的、潜在的致命疾病，这要么是因为1)患者没有参加筛查计划，2)该计划没有及早发现疾病以便治愈，要么是3)所选的治疗方法没有根除疾病。与此同时，许多男性经过多年不必要的筛查和/或被诊断为前列腺癌，转移率较低。需要的是识别患有前列腺癌的高风险但死于前列腺癌的高风险的男性的标志物。在疾病发展之前识别高危男子将允许进行密集的筛查和/或预防，同时使那些低风险的人免于数年的筛查。在确诊后识别高危男性将允许进行有针对性的治疗，同时避免那些低风险的潜在病态治疗。我们相信，对常见多态变异的分析将准确地进行这种风险分层。这项应用的目的是确定哪些DNA多态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记物。我们建议进行一项病例对照研究，以转移性前列腺癌患者为我们的病例，以很少或没有发生前列腺癌风险的人作为对照，以确定与晚期前列腺癌相关的多态变异。这项提议有两个具体目标。(I)建立晚期前列腺癌患者和种族匹配对照的体细胞DNA数据库。(Ii)研究基因型别与晚期前列腺癌风险之间的关系。研究转移性疾病患者的理由有两个。首先，患有转移性疾病的患者明确患有临床上重要的前列腺癌。因此，没有患者与惰性疾病有明显的联系。其次，由于这些患者的早期识别有可能产生最大的影响，他们是应该被研究的患者。在这项研究结束时，我们将有一组标志物，有可能在未来的前瞻性研究中预测哪些患者最终死于前列腺癌的风险很高。

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.