5ALPHA REDUCTASE GENOTYPE, RACE AND PROSTATE CANCER RISK

在美国，每年有近20万名男性被诊断为前列腺癌 每年造成约3.8万人死亡。在此应用程序中，我们 打算采取分子流行病学的方法来检查我们的中心 前列腺癌风险主要受以下因素影响的假说 人类5α-还原酶II(SRD5A2)基因的特定基因类型。 我们建议用分子研究以下七个特定的目标 遗传和流行病学工具：1)确定 SRD5A2基因与前列腺癌的关系 男性SRD5A2基因的DNA标记[TA-STR] 患有前列腺癌和来自非裔美国人和白人的配对对照 患前列腺癌的风险大相径庭的男性。2)对DNA进行表征 SRD5A2基因的序列变异使男性易患前列腺癌 通过对少数非裔美国人和白人的DNA测序发现癌症 携带高危SRD5A2基因的前列腺癌患者 在(1)中识别，从而确定生殖系的确切性质 易患前列腺癌的DNA改变。3)对DNA进行表征 SRD5A2基因的序列变异可能保护亚洲男性 通过对一小部分正常人(对照)的DNA测序发现前列腺癌 亚洲男性双氢睾丸酮(DHT)水平较低，因此 确定可能具有保护作用的生殖系DNA改变 前列腺癌。4)生化性质(酶)测定 (2)和(3)中确定的每个序列变异的活性)。这将是 区分不相关的多态和实际的活动改变 突变。5)确定SRD5A2基因与 前列腺癌基因分型[使用相关序列变异 在(4)中确定的SRD5A2基因在三个种族-民族[亚裔- 美国人(这里定义为华裔和日裔美国人)，非洲人- [美国人和白人]前列腺癌病例和匹配的对照组。6)至 根据第(5)项中确定的关联的强度利用结果 以及这些等位基因在三个种族-民族群体中的流行率，到 估计SRD5A2基因在解释变异中的作用 在这三组男性中前列腺癌风险的 患前列腺癌的风险不同。7)进一步描述 SRD5A2基因在前列腺癌中的体细胞定义 这种基因的突变。

Prostate cancer is diagnosed in almost 200,000 men every year in the US and accounts for about 38,000 annual deaths. In this application, we intend to take a molecular epidemiologic approach to examining our central hypothesis that risk of prostate cancer is substantially influenced by specific genotypes in the human 5alpha-reductase type II (SRD5A2) gene. We propose to investigate the following seven specific aims with molecular genetic and epidemiologic tools: 1) To determine the relationship between the SRD5A2 gene and prostate cancer by genotyping a particular polymorphic DNA marker [TA short tandem repeat (TA-STR)] in the SRD5A2 gene in men with prostate cancer and matched controls from African-American and White men at widely different risks of prostate cancer. 2) To characterize DNA sequence variations in the SRD5A2 gene that predispose men to prostate cancer by sequencing DNA from a small number of African-American and White men with prostate cancer, who carry the high risk SRD5A2 genotypes identified in (1), and so to determine the precise nature of the germline DNA alterations predisposing to prostate cancer. 3) To characterize DNA sequence variations in the SRD5A2 gene that may protect Asian men from prostate cancer by sequencing DNA from a small number of normal (control) Asian men who have low levels of dihydrotestosterone (DHT), and so to determine the germline DNA alterations which may be protective against prostate cancer. 4) To determine the biochemical properties (enzyme activity) of each sequence variation identified in (2) and (3). This will distinguish irrelevant polymorphisms from actual activity altering mutations. 5) To determine the relationship between the SRD5A2 gene and prostate cancer by genotyping [using the relevant sequence variations identified in (4)] the SRD5A2 gene in three racial-ethnic groups [Asian- Americans (defined here as Chinese- and Japanese-Americans), African- Americans and Whites] of prostate cancer cases and matched controls. 6) To utilize the results on the strength of the associations identified in (5) and the prevalence of these alleles in the three racial-ethnic groups, to estimate the contribution of SRD5A2 genotype in explaining the variation in prostate cancer risk among these three groups of men at widely differing risk of prostate cancer. 7) To further characterize the involvement of the SRD5A2 gene in prostate cancer by defining somatic mutations in this gene.