Project 1

雄激素受体（AR）在前列腺癌（PCa）的肿瘤生长和进展中起着核心作用。非裔美国人（AA）男性的前列腺癌发病率和死亡率高于白种人。这种差异可能部分与AA男性前列腺组织中AR的表达或活性有关，或者与AR的独特突变或多态性有关。在白种人中，AR突变在局部肿瘤中不常见（<2%），但在晚期、转移性和激素难治性疾病中发生的频率更高。在AAs中，原发性PCa中AR突变的患病率、临床和生物学意义尚不清楚。我们在一名患有未经治疗的器官局限性前列腺癌的AA患者建立的PCa细胞系（E006AA）中发现了AR的基因组扩增和体细胞突变。此外，在60例器官限制性根治性前列腺切除术样本（30例AA患者和30例高加索患者）中，我们仅在AA患者中发现了4个AR突变。此外，我们在一个家族性PCa的AA家族中发现了一种新的AR种系错义突变。根据这些观察结果，我们假设AR突变的多样性和高流行率对散发性或家族性前列腺癌在AAs中的生物学和临床侵袭性和/或进展起着重要作用。在Specific Aim 1中，我们将确定500例AA男性原发性未经治疗的前列腺癌根治性前列腺切除术标本中激光捕获细胞中AR突变的频率和类型，以及它们与反映前列腺癌临床进展或侵袭性的预测或预后因素（如Gleason评分、PSA）的关系。在特异性目标2中，我们将确定家族性PCa在AAs中种系突变的患病率。我们会把分析范围扩大到所有正常人和受前列腺癌影响的人

The Androgen receptor (AR) plays a central role in neoplastic growth and progression of prostate cancer (PCa). The PCa incidence and mortality rate is higher in African-American (AA) men than in Caucasians. This disparity may be related in part to the expression or activity of AR in the prostate tissue of AA men or to unique mutations or polymorphisms of the AR. In Caucasians, AR mutations are infrequent (<2%) in localized tumors, but occur at a higher frequency in advanced, metastatic, and hormone-refractory disease. In AAs, the prevalence, clinical, and biological significance of AR mutations in primary PCa are unknown. We discovered genomic amplification and somatic mutations of AR in a PCa cell line (E006AA) we established from an AA patient with an untreated organ-confined PCa. In addition, in a set of 60 organ-confined radical prostatectomy samples (30 AAs and 30 Caucasians), we identified 4 AR mutations in AA patients only. Furthermore, we discovered a novel AR germline missense mutation in several PCa-affected members in an AA family with familial PCa. From these observations, we hypothesize that diversity and a high prevalence of AR mutations contribute significantly to biological and clinical aggressiveness and/or progression of sporadic or familial PCa in AAs. In Specific Aim 1, we will determine the frequency and type of AR mutations in laser-captured cells from radical prostatectomy specimens in 500 AA men with primary untreated PCa and their association with predictive or prognostic factors (e.g., Gleason's score, PSA) reflecting clinical progression or aggressiveness of PCa. In Specific Aim 2, we will determine the prevalence of the germline mutation in familial PCa in AAs. We will extend our analysis to all normal and PCa-affected members of 40 high-risk AA and Caucasian families and an additional pool of 400 normal unrelated individuals from both ethnic cohorts. In Specific Aim 3, we will determine the biological activities of the identified AR mutations in AR-negative PCa cells. Functional characterization will be limited only to those mutations identified in tumors with clinically or histopathologically aggressive features. The result will provide insight enabling the critical assessment of the AR gene in PCa predisposition and progression in AAs.