5 ALPHA REDUCTASE GENOTYPE, RACE PROSTATE CANCER RISK

5 α还原酶基因型，种族前列腺癌风险

• 批准号: 6376184
• 负责人: JUERGEN K REICHARDT
• 金额: $ 43.15万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376184
• 关键词: African American; Asian Americans; androstane compound; cancer risk; clinical research; enzyme activity; gene mutation; genetic polymorphism; genetic susceptibility; genotype; human genetic material tag; human subject; male; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplastic process; nucleic acid sequence; prostate neoplasms; racial /ethnic difference; steroid hormone metabolism; testosterone; testosterone 5 alpha reductase

DESCRIPTION: (Adapted from the Investigator's Abstract) Prostate cancer is currently the most common cancer among American men. Regulation of prostatic cell growth is largely controlled by androgens including especially dihydrotestosterone (DHT). This compound is synthesized from the male hormone testosterone by the enzyme 5-alpha reductase which is encoded in the prostate by the SRD5A2 gene. The etiology of prostate cancer appears to include increased steroid 5-alpha reductase activity particularly across racial/ethnic groups which are at very different risk for prostate cancer, such as high-risk African-Americans and lower risk Asians, the two extreme groups for risk. We have identified and characterized genetic variability in the SRD5A2 gene among various racial/ethnic groups in the US and between prostate cancer cases and controls. These investigations made use of a large multiethnic cohort in Los Angeles and Hawaii. We propose to build on and expand our studies of the SRD5A2 gene and prostate cancer by epidemiologic, genetic and biochemical methods. It is our overall hypothesis that genetic variation at the SRD5A2 locus plays a significant role in predisposition to and progression of prostate cancer and in explaining the racial/ethnic variation of risk. To this end, we intend to investigate the following interrelated six specific aims: 1) To identify all constitutional ("germline") DNA variations across the entire SRD5A2 gene that might contribute to predisposition to prostate cancer; 2) To determine the relationship between each variant identified in Specific Aim 1 to prostate cancer risk in for racial/ethnic populations: 4) To identify somatic mutations in the SRD5A2 gene involved in prostate cancer progression; 5) To characterize the biochemical properties of the somatic DNA genetic variants identified in Specific aims 1 and 4 in an in vitro model system; 6) To determine the contribution of somatic DNA genetic variants in the SRD5A2 gene to prostate cancer progression within and across racial/ethnic groups. Therefore, we will investigate the molecular basis of predisposition to prostate cancer and its progression in a multidisciplinary study rooted in molecular epidemiology with significant implications for presymptomatic identification of at-risk individuals, targeted chemoprevention and improved treatment of this disease.

描述：（改编自研究者摘要）前列腺癌是 目前是美国男性中最常见的癌症。前列腺的调节 细胞生长很大程度上受雄激素控制，尤其是 二氢睾酮（DHT）。这种化合物是由雄性激素合成的 睾酮由前列腺中编码的 5-α 还原酶产生 由 SRD5A2 基因决定。前列腺癌的病因似乎包括 类固醇 5-α 还原酶活性增加，尤其是跨种族/民族 前列腺癌风险差异很大的群体，例如高风险群体 非裔美国人和风险较低的亚洲人是两个极端的风险群体。我们 已鉴定并表征了 SRD5A2 基因的遗传变异性 美国各个种族/族裔群体以及前列腺癌病例和 控制。这些调查利用了洛杉矶的一个大型多种族群体 安吉利斯和夏威夷。我们建议以 SRD5A2 为基础并扩展我们的研究 基因和前列腺癌的流行病学、遗传学和生化方法。它 我们的总体假设是 SRD5A2 基因座的遗传变异起着 在前列腺癌的易感性和进展中发挥着重要作用 解释风险的种族/民族差异。为此，我们打算 研究以下相互关联的六个具体目标： 1) 确定所有 整个 SRD5A2 基因的组成（“种系”）DNA 变异 可能会导致前列腺癌的易感性； 2）确定 具体目标 1 中确定的每个变体与前列腺之间的关系 种族/民族人群的癌症风险：4) 识别体细胞突变 SRD5A2 基因参与前列腺癌进展； 5）表征 体细胞 DNA 遗传变异体的生化特性 体外模型系统中的具体目标 1 和 4； 6) 确定 SRD5A2 基因体细胞 DNA 遗传变异对前列腺的影响 种族/族裔群体内部和跨种族/族裔群体的癌症进展。因此，我们将 研究前列腺癌易感性的分子基础及其 根植于分子流行病学的多学科研究进展 对症状前识别高危人群具有重要意义 个体，有针对性的化学预防和改善这种疾病的治疗。