Genetic Susceptibility for Prostate Cancer Progression

描述（由申请人提供）：2004年在美国估计有220900名男性被诊断患有前列腺癌；大约一半的人将接受根治性前列腺切除术（RP）来治疗他们的疾病。多达25%或更多接受这种治疗的男性会在几个月到几年后再次出现血清前列腺特异性抗原（PSA）水平的升高。前列腺切除术后PSA升高，称为生化复发或失败，是前列腺癌细胞在前列腺切除术前逃逸（转移）增殖的明确指示。据统计，超过三分之一的男性生化复发发展为临床可检测的转移性疾病（Pound 1999）。在美国，这种无法治愈的致命阶段的前列腺癌每年夺去超过29,000人的生命。临床医生无法确定地预测哪些男性可能治疗失败并随后发展为转移性疾病，哪些不会。我们假设RP治疗前列腺癌后疾病复发的可能性是由调节前列腺癌转移的基因序列变异修饰和/或决定的。重申这一假设，遗传背景是转移潜力的决定因素。本应用程序的具体目的是：1)在接受根治性前列腺切除术治疗临床局限性前列腺癌的男性病例对照人群中，探讨转移相关基因的遗传变异与疾病进展之间的关系；病例为手术治疗后疾病进展的男性，对照组为疾病未进展的男性；2)对于显示与特异性Aim 1进展相关的基因，在第二个相似的病例对照人群中确认其相关性；3)对于两种人群的相关基因，进行精细定位关联测试，并评估非欧裔美国人病例的关联；4)评估进展相关基因的基因型-表型相关性。我们期望这项研究将为前列腺癌进展机制提供新的见解，并为识别这一威胁生命事件的高风险男性提供基础。

DESCRIPTION (provided by applicant): Of the 220,900 men estimated to be diagnosed with prostate cancer in 2004 in the U.S; about one half will undergo radical prostatectomy (RP) for treatment of their disease. As many as 25% or more men who undergo this treatment will experience a re-elevation in their serum Prostate Specific Antigen (PSA) level within months to years later. This rise in PSA after prostatectomy, termed biochemical recurrence or failure, is a clear indication of the proliferation of prostate cancer cells which escaped (metastasized) prior to prostatectomy. Statistically, more than one-third of men with biochemical recurrence develop clinically detectable metastatic disease (Pound 1999). This non-curable, lethal stage of prostate cancer claims over 29,000 lives in the U.S. annually. Clinicians are unable to predict with certainty which men are likely to fail therapy and subsequently develop metastatic disease and which are not. We hypothesize that the likelihood of disease recurrence after treatment of prostate cancer by RP is modified and/or determined by sequence variation in genes that regulate prostate cancer metastasis. Restating this hypothesis, genetic background is a determinant of metastatic potential. The Specific Aims of this application are: 1) Explore the association between genetic variants in metastasis-related genes and disease progression in a case-control population of men who have undergone radical prostatectomy for treatment of clinically localized prostate cancer; cases are men whose disease progressed after surgical therapy, and controls are men whose disease did not progress; 2) For genes demonstrating association with progression in Specific Aim 1, confirm the association in a second, similar case-control population; 3) For genes associated in both populations, perform fine-mapping association tests, and assess association in non-European Americans cases; 4) Assess genotype - phenotype correlation for progression associated genes. We anticipate that this study will provide novel insights into the mechanisms responsible for prostate cancer progression, and provide a basis for the identification of men at elevated risk for this life threatening event.