Project 1

雄激素受体(AR)在前列腺癌(PCa)的肿瘤生长和进展中起核心作用。非洲裔美国人(AA)的前列腺癌发病率和死亡率高于高加索人。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，也可能与AR的独特突变或多态有关。在高加索人中，AR突变在局部肿瘤中很少见(&lt；2%)，但在晚期、转移性和激素难治性疾病中发生频率较高。在AAS中，原发PCa中AR突变的患病率、临床和生物学意义尚不清楚。我们在我们从一名患有未经治疗的器官受限的前列腺癌患者建立的前列腺癌细胞系(E006AA)中发现了AR的基因组扩增和体细胞突变。此外，在一组60例器官受限的前列腺癌根治术样本中(30名AA和30名高加索人)，我们仅在AA患者中发现了4个AR突变。此外，我们在一个有家族性前列腺癌的AA家族中发现了一种新的AR胚系错义突变。根据这些观察，我们假设AR突变的多样性和高流行率对AAS中散发性或家族性PCa的生物学和临床侵袭性和/或进展有显著贡献。在具体目标1中，我们将确定500名未经治疗的AA男性前列腺癌患者根治性前列腺癌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PCa临床进展或侵袭性的预测或预后因素(例如Gleason评分，PSA)的相关性。在特定的目标2中，我们将确定AAS家族性PCa中胚系突变的发生率。我们将把我们的分析扩展到所有正常的和受PCA影响的 来自40个高风险再生障碍性贫血和高加索家庭的成员，以及来自这两个民族队列的另外400名正常的无血缘关系的人。在特定的目标3中，我们将确定在AR阴性的PCa细胞中已识别的AR突变的生物学活性。功能特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发现的那些突变。这一结果将为对AR基因在前列腺癌易感性和进展中的关键评估提供洞察力。

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.