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重要作用。非裔美国人（AA）男性的PCa发病率和死亡率高于白人。这种差异可能与AA男性前列腺组织中AR的表达或活性或AR的独特突变或多态性部分相关。在高加索人中，AR突变在局部肿瘤中不常见（<2%），但在晚期、转移性和难治性疾病中发生频率较高。在AA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。我们发现基因组扩增和体细胞突变的AR在PCa细胞系（E006 AA），我们建立了从AA患者与未经治疗的器官局限性PCa。此外，在一组60个器官限制性根治性乳腺癌切除术样本（30个AA和30个高加索人）中，我们仅在AA患者中发现了4个AR突变。此外，我们发现了一个新的AR生殖细胞错义突变的几个PCA影响的成员在AA家族与家族性PCa。根据这些观察，我们假设AR突变的多样性和高患病率显著促进AA中散发性或家族性PCa的生物学和临床侵袭性和/或进展。在具体目标1中，我们将确定500名患有原发性未经治疗的PCa的AA男性根治性前列腺切除术标本中激光捕获细胞中AR突变的频率和类型及其与预测或预后因素（例如，Gleason评分，PSA）反映PCa的临床进展或侵袭性。在特定目标2中，我们将确定AA中家族性PCa中生殖系突变的患病率。我们将把我们的分析扩展到所有正常的和PCA影响的 40个高风险AA和白人家庭的成员和另外400个来自两个种族队列的正常无关个体。在特定目标3中，我们将确定AR阴性PCa细胞中已鉴定AR突变的生物学活性。功能表征将仅限于在具有临床或组织病理学侵袭性特征的肿瘤中鉴定的那些突变。结果将提供洞察力，使PCa易感性和AA进展中的AR基因的关键评估。

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.