Genetic Susceptibility for Prostate Cancer Progression

描述（由申请人提供）：在2004年美国估计诊断为前列腺癌的220，900名男性中，约一半将接受根治性前列腺切除术（RP）以治疗其疾病。多达25%或更多的接受这种治疗的男性将在数月至数年后经历血清前列腺特异性抗原（PSA）水平的重新升高。前列腺切除术后PSA升高，称为生化复发或失败，是前列腺切除术前逃逸（转移）的前列腺癌细胞增殖的明确指示。据统计，超过三分之一的生化复发男性发生临床可检测的转移性疾病（磅1999）。这种不可治愈的致命阶段的前列腺癌每年在美国夺去超过29，000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，随后发生转移性疾病，哪些不会。我们假设，通过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中的序列变异修改和/或确定的。重申这一假设，遗传背景是转移潜力的决定因素。本申请的具体目的是：1）探索转移相关基因中的遗传变异与已经经历根治性前列腺切除术以治疗临床局限性前列腺癌的男性病例对照群体中的疾病进展之间的关联;病例是手术治疗后疾病进展的男性，对照是疾病没有进展的男性; 2）对于证明与特定目标1中的进展相关的基因，在第二个相似的病例对照群体中确认该关联; 3）对于两个群体中相关的基因，进行精细作图关联检验，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，并为确定这种危及生命的事件的风险升高的男性提供依据。

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.