VARIATION OF THE HSD17B3 GENE AND PROSTATE CANCER

HSD17B3 基因变异与前列腺癌

• 批准号: 2907324
• 负责人: JUERGEN K REICHARDT
• 金额: $ 7.79万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2907324
• 关键词: African American; Asian Americans; Hispanic Americans; androgens; cancer risk; clinical research; complementary DNA; gene expression; genetic polymorphism; genetic susceptibility; hormone regulation /control mechanism; human genetic material tag; human subject; hydroxysteroid dehydrogenases; male; neoplasm /cancer genetics; point mutation; polymerase chain reaction; prostate neoplasms; racial /ethnic difference

Regulation of prostatic cell growth is controlled, at least in part by steroid hormones and particularly androgens or male hormones. Epidemiological investigations have revealed that testosterone levels are relatively high in African-Americans and lower in Asians and Caucasians, a pattern that is reminiscent of the risk for developing prostate cancer among racial/ethnic groups. The normal (and abnormal) genetic variations in steroid hormone-metabolic genes in human populations are only poorly characterized and not well understood at this time. It is our hypothesis that genetic variants of human androgen- metabolic enzymes contribute significantly to androgen levels and risk for prostate cancer. We propose to identify and characterize in genetic and biochemical detail common cSNPs (coding region single nucleotide polymorphisms) in a human hormone-metabolic genes with relevance to predisposition to prostate cancer and male reproductive biology in general, the HSD17B3 gene which encodes the testicular or type III 17beta- hydroxysteroid dehydrogenase enzyme. This enzyme converts the precursor adrostenedione into testosterone, the male hormone. We propose to identify cSNPs in four large racial/ethnic population in the US: African-Americans, Asians, Caucasians and Latinos that are also at very different risk for prostate cancer. African- Americans have a very high risk for the disease, while Asians have relatively low risk. CSNPs will be identified by automated DNA sequencing of PCR (polymerase chain reaction)-amplified exonic DNA. Missense mutations will be reconstructed in the cDNA and over- expressed to assess the functional significance of these particular cSNPs. Thus, we intend to investigate the following two specific aims: 1) To identify constitutional ("germline") DNA mutations (particularly cSNPs) in a male hormone-metabolic gene, HSD17B3, in four racial/ethnic groups; and 2) to establish the in vitro biochemical properties of all missense mutations identified in 1. In summary, we will investigate the molecular genetics of natural variation in an androgen-metabolic gene in four different racial/ethnic populations. Our studies will have relevance to the understanding of predisposition to prostate cancer as well as male reproductive biology and its aberrations. The investigations proposed here will lead to a molecular epidemiologic analysis of prostate cancer risk in various racial/ethnic groups.

前列腺细胞生长的调节至少部分受到类固醇激素、特别是雄激素或雄性激素的控制。流行病学调查显示，非裔美国人的睾酮水平相对较高，而亚洲人和白种人的睾酮水平较低，这种模式让人想起种族/族裔群体中患前列腺癌的风险。目前，人类类固醇激素代谢基因的正常（和异常）遗传变异的特征还很不清楚，也没有得到很好的了解。我们的假设是，人类雄激素代谢酶的遗传变异对雄激素水平和前列腺癌的风险有显着影响。我们建议鉴定和表征人类激素代谢基因中与前列腺癌易感性和男性生殖生物学相关的常见 cSNP（编码区单核苷酸多态性）的遗传和生化细节，HSD17B3 基因编码睾丸或类型III 17β-羟基类固醇脱氢酶。这种酶将前体雄烯二酮转化为睾酮，即雄性激素。我们建议在美国四大种族/族裔人群中识别 cSNP：非裔美国人、亚洲人、白种人和拉丁裔，他们患前列腺癌的风险也截然不同。非裔美国人患这种疾病的风险非常高，而亚洲人的风险相对较低。 CSNP 将通过 PCR（聚合酶链式反应）扩增的外显子 DNA 的自动 DNA 测序来鉴定。错义突变将在 cDNA 中重建并过度表达，以评估这些特定 cSNP 的功能意义。因此，我们打算研究以下两个具体目标： 1) 鉴定四个种族/族裔群体中雄性激素代谢基因 HSD17B3 的组成性（“种系”）DNA 突变（特别是 cSNP）； 2) 确定1中确定的所有错义突变的体外生化特性。总之，我们将研究四个不同种族/民族群体中雄激素代谢基因自然变异的分子遗传学。我们的研究将与了解前列腺癌的易感性以及男性生殖生物学及其畸变相关。这里提出的研究将对不同种族/族裔群体的前列腺癌风险进行分子流行病学分析。