Genetic Susceptibility for Prostate Cancer Progression

描述(申请人提供)：在美国2004年估计被诊断为前列腺癌的220,900名男性中，约有一半将接受根治性前列腺切除术(RP)来治疗他们的疾病。多达25%或更多的男性接受这种治疗后，他们的血清前列腺特异性抗原(PSA)水平将在几个月到几年后再次上升。前列腺切除术后PSA的升高，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)的明显迹象。据统计，超过三分之一的生化复发男性发展为临床可检测到的转移性疾病(庞德1999)。这种无法治愈的致命前列腺癌在美国每年夺走超过2.9万人的生命。临床医生无法肯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，哪些不是。我们假设，前列腺癌RP治疗后疾病复发的可能性是由调节前列腺癌转移的基因的序列变异改变和/或决定的。重申这一假设，遗传背景是转移潜力的决定因素。这项应用的具体目的是：1)在接受前列腺癌根治术治疗临床局限性前列腺癌的病例对照人群中探索转移相关基因的遗传变异与疾病进展之间的关联；病例是经过手术治疗后疾病进展的男性，而对照是疾病没有进展的男性；2)对于在特定目标1中表明与疾病进展相关的基因，确认在第二个相似的病例对照人群中的关联；3)对于两个人群中的相关基因，进行精细定位关联测试，并评估非欧洲裔美国人病例中的关联；4)评估进展相关基因的基因型-表型相关性。我们预计，这项研究将为前列腺癌进展的机制提供新的见解，并为识别这一危及生命的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.