Cell Cycle Variants and Metastatic Prostate Cancer Risk

细胞周期变异和转移性前列腺癌风险

• 批准号: 6859610
• 负责人: ADAM S KIBEL
• 金额: $ 24.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-08 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859610
• 关键词: cell cycle; clinical research; cytogenetics; early diagnosis; genetic markers; genetic susceptibility; human genetic material tag; human mortality; human subject; longitudinal human study; male; metastasis; neoplasm /cancer diagnosis; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; prognosis; prostate neoplasms; single nucleotide polymorphism

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.

描述（由申请人提供）：基于PSA的筛查已导致前列腺癌病例的数量急剧增加，并导致疾病最近死亡的死亡率下降。但是，这种成功是有代价的：对其他人的某些和无效治疗的过度诊断和过度治疗。由于超过80％的男性患有组织学前列腺癌，因此2004年的关键问题不是谁面临患上前列腺癌的风险，而是有患致命前列腺癌的风险。在诊断前识别那些具有侵略性和潜在致命前列腺癌的高风险的男性，将允许在低风险筛查年度的较低风险年份中散发出强烈的筛查和/或预防。在诊断时鉴定高风险患者将针对个人进行侵略性治疗，同时保留那些潜在病态治疗的风险较低的人。由于已经假设转移潜能至少部分由宿主遗传背景确定，因此得出的是，对常见多态性变体的分析将被证明是确定谁面临致命前列腺癌风险的有用筛查工具。我们建议进行一项案例控制研究，以识别转移性疾病的易感基因座，然后在包括前瞻性获得的患者人群在内的其他同龄人中验证我们的发现。我们选择了细胞周期中的基因作为候选物，因为有很多数据证明1）细胞周期基因的细微基因组变化增加了动物模型中癌症的风险，2）变异改变细胞周期基因中的基因功能，最后3）细胞周期内的遗传变异基因中的遗传变异与侵袭性前列腺癌有关。该提案的三个具体目的是：（i）在细胞周期调节基因中多态性和转移性前列腺癌风险增加之间寻找关联。 （2）确定AIM 1中鉴定出的风险等位基因是通过研究其他患者人群而普遍的转移性前列腺癌或前列腺癌的预测指标。 （3）建立一个前瞻性队列以确定高风险SNP是否可以预测治疗失败的风险。在这项研究的结论中，我们将有一个标记面板，可用于预测哪些患者患有治疗失败的高风险和前列腺癌死亡。