Cell Cycle Variants and Metastatic Prostate Cancer Risk

描述（由申请人提供）：基于PSA的筛查有助于前列腺癌病例数量的急剧增加和最近该疾病死亡率的下降。然而，这一成功是有代价的：对一些人过度诊断和过度治疗，对另一些人无效治疗。由于80%以上的男性会发展为组织学前列腺癌，2004年的关键问题不是谁有发展前列腺癌的风险，而是谁有发展致命前列腺癌的风险。在诊断前识别那些具有侵袭性和潜在致命性前列腺癌高风险的男性将允许在筛选低风险年的同时进行密集的筛选和/或预防。在诊断时识别高风险患者将针对个体进行积极治疗，同时使低风险患者免于潜在的病态治疗。由于它已被假设，转移潜力至少部分地由宿主遗传背景决定，因此，分析常见的多态性变异将被证明是一个有用的筛选工具，以确定谁是致命的前列腺癌的风险。我们建议进行一项病例对照研究，以确定转移性疾病的易感基因位点，然后在包括前瞻性获得的患者人群在内的其他队列中验证我们的研究结果。我们选择细胞周期中的基因作为我们的候选基因，因为有大量数据表明：1）细胞周期基因中的细微基因组变化会增加动物模型中的癌症风险，2）变异改变细胞周期基因中的基因功能，最后3）细胞周期基因中的遗传变异与侵袭性前列腺癌相关。本研究的三个具体目标是：（1）寻找细胞周期调控基因多态性与转移性前列腺癌风险增加之间的关联。(2)通过研究其他患者人群，确定目标1中确定的风险等位基因是否是转移性前列腺癌的特异性预测因子或一般前列腺癌的预测因子。(3)建立一个前瞻性队列，以确定高风险SNP是否可预测治疗失败的风险。在这项研究结束时，我们将有一组标记物，可用于预测哪些患者处于治疗失败和最终死于前列腺癌的高风险中。

DESCRIPTION (provided by applicant): PSA based screening has contributed to a dramatic increase in the number of prostate cancer cases and to a recent fall in mortality from the disease. However, this success has come at a cost: over-diagnosis and over-treatment for some and ineffectual treatment for others. Since upwards of 80% of men develop histologic prostate cancer, the critical question in 2004 is not who is at risk for developing prostate cancer, but who is at risk for developing lethal prostate cancer. Identification of those men at high risk for aggressive and potentially lethal prostate carcinoma prior to diagnosis would allow intense screening and/or prophylaxis while spading individuals at low risk years of screening. Identification of high risk patients at the time of diagnosis would target individuals for aggressive therapy while sparing those at low risk from potentially morbid treatment. Since it has been hypothesized that metastatic potential is determined at least in part by host genetic background, it follows that analysis of common polymorphic variants will prove to be a useful screening tool to determine who is at risk for lethal prostate carcinoma. We propose to perform a case control study to identify susceptibility loci for metastatic disease and then to validate our findings in additional cohorts including a prospectively acquired patient population. We have chosen genes in the cell cycle as our candidates because there are abundant data demonstrating 1) subtle genomic changes in cell cycle genes increase risk of cancer in animal models, 2) variants alter gene function in cell cycle genes and lastly 3) genetic variants within cell cycle genes are associated with aggressive prostate carcinoma. The three specific aims of this proposal are: (I) To search for associations between polymorphisms in cell cycle regulatory genes and increased risk of metastatic prostate carcinoma. (2) To determine if risk alleles identified in Aim 1 are predictors of metastatic prostate carcinoma specifically or prostate cancer in general by studying additional patient populations. (3) To establish a prospective cohort to determine if high risk SNPs are predictive of risk for treatment failure. At the conclusion of this study, we will have a panel of markers that can be used to predict which patients are at high risk of treatment failure and eventual death from prostate carcinoma.