Cell Cycle Variants and Metastatic Prostate Cancer Risk

描述（由申请人提供）：基于PSA的筛查导致前列腺癌病例数量的急剧增加，并导致该疾病的死亡率最近下降。然而，这一成功是有代价的：一些人过度诊断和过度治疗，另一些人治疗无效。由于超过80%的男性患有组织学前列腺癌，2004年的关键问题不是谁有患前列腺癌的风险，而是谁有患致命性前列腺癌的风险。在诊断前确定那些具有侵袭性和潜在致命性前列腺癌高风险的男性，可以进行密集的筛查和/或预防，同时分散低风险个体的筛查年限。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。由于已经假设转移潜能至少部分由宿主遗传背景决定，因此对常见多态性变异的分析将被证明是确定谁有致死性前列腺癌风险的有用筛查工具。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性位点，然后在其他队列（包括前瞻性获得的患者群体）中验证我们的发现。我们选择细胞周期中的基因作为我们的候选基因，因为有大量的数据表明：1)在动物模型中，细胞周期基因中细微的基因组变化增加了癌症的风险；2)变异改变了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有关。本提案的三个具体目的是：(1)寻找细胞周期调节基因多态性与转移性前列腺癌风险增加之间的关联。(2)通过研究额外的患者群体，确定Aim 1中确定的风险等位基因是转移性前列腺癌的特异性预测因子还是前列腺癌的总体预测因子。(3)建立前瞻性队列，以确定高风险snp是否可预测治疗失败风险。在这项研究的结论，我们将有一组标志物，可用于预测哪些患者在治疗失败和最终死亡的高风险前列腺癌。

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.