Project 1

项目1

基本信息

批准号：
8102545
负责人：
BETTY P. DENNIS
金额：
$ 28.5万
依托单位：
DILLARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-16 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8102545
关键词：
Address Affect Affinity African American Age Alleles Androgen Antagonists Androgen Receptor Androgen Response Element Androgens Base Sequence Benign Binding Biological Biological Assay Cancer Family Caucasians Caucasoid Race Cell Line Cells Characteristics Clinical Codon Nucleotides DNA DNA Binding Domain Disease Disease Progression Event Exons Family Family Study Family history of Frequencies Gene Targeting Genetic Polymorphism Genomics Genotype Germ-Line Mutation Gleason Grade for Prostate Cancer High Prevalence Hormones In Vitro Incidence Individual Laboratories Lasers Lead Length Linkage Disequilibrium Malignant - descriptor Malignant neoplasm of prostate Missense Mutation Molecular Mutation Natural History Neoplasms Oligonucleotides Organ PC3 cell line Patients Play Predisposition Prevalence Prognostic Factor Prostate Prostate-Specific Antigen Radical Prostatectomy Receptor Gene Refractory Refractory Disease Reporter Genes Role Sampling Site-Directed Mutagenesis Somatic Mutation Specimen Staging Testing Tissues Transactivation Transfection cancer cell cancer site cell type clinically relevant clinically significant cohort ethnic difference high risk improved insight member men mortality mutant novel outcome forecast prognostic prostate carcinogenesis protein expression receptor receptor expression receptor-mediated signaling response restriction enzyme steroid hormone tumor

项目摘要

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.

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PCA发病率和死亡率高于高加索人。这种差异可能部分与AA人的前列腺组织中AR的表达或活性有关，或与AR的独特突变或多态性有关。在高加索人中，AR突变在局部肿瘤中很少发生（<2％），但在晚期，转移性和激素难治性疾病中以较高的频率发生。在AAS中，AR突变在原发性PCA中的患病率，临床和生物学意义尚不清楚。我们在PCA细胞系（E006AA）中发现了我们从具有未处理器官的PCA的AA患者建立的PCA细胞系（E006AA）中AR的基因组扩增和体细胞突变。此外，在一组60个器官的根治性前列腺切除术样品（30个AAS和30种高加索人）中，我们仅在AA患者中鉴定出4个AR突变。此外，我们在一个具有家族性PCA的AA家族中的几个受PCA影响的成员中发现了一个新颖的AR种系错线突变。从这些观察结果中，我们假设AR突变的多样性和高流行率对AAS中零星或家族性PCA的生物学和临床攻击性和/或进展显着贡献。在特定目标1中，我们将确定500个未经治疗的PCA的500名AA男性的激光捕获细胞中AR突变的频率和类型，及其与预测性或预后因素（例如GLEASON的分数，PSA）的关联，反映了PCA的临床进展或攻击性。在特定目标2中，我们将确定AAS家族性PCA中种系突变的流行率。我们将把分析扩展到所有正常和受PCA影响的来自两个族裔队列的40个高风险AA和高加索家庭的成员以及由400个普通无关的个体组成的量。在特定的目标3中，我们将确定AR阴性PCA细胞中鉴定出的AR突变的生物学活性。功能表征仅限于在具有临床或组织病理学攻击性特征的肿瘤中鉴定出的突变。结果将提供洞察力，从而使PCA易感性和AAS进展中AR基因的关键评估。