5ALPHA REDUCTASE GENOTYPE, RACE AND PROSTATE CANCER RISK

在美国，每年有近20万男性被诊断出患有前列腺癌。 每年约有38,000人因此死亡 在本申请中，我们 打算采用分子流行病学方法来检查我们的中心 假设前列腺癌的风险在很大程度上受到 人5 α-还原酶II型（SRD 5A 2）基因中的特定基因型。 我们建议研究以下七个具体目标与分子 遗传学和流行病学工具：1）确定 SRD 5A 2基因与前列腺癌的基因分型 男性SRD 5A 2基因中的DNA标记[TA短串联重复序列（TA-STR）] 与来自非裔美国人和白色人的对照组 男性患前列腺癌的风险差异很大。2)为了表征DNA SRD 5A 2基因的序列变异使男性易患前列腺疾病 通过对少数非洲裔美国人和白色人的DNA进行测序， 携带高危SRD 5A 2基因型的前列腺癌男性 在（1）中鉴定，从而确定生殖系的精确性质 DNA改变易患前列腺癌。3)为了表征DNA SRD 5A 2基因的序列变异可能保护亚洲男性免受 通过对少量正常人（对照）的DNA进行测序， 亚洲男性谁有低水平的双氢睾酮（DHT），所以， 确定生殖系DNA改变，这可能是保护免受 前列腺癌4)为了确定生物化学性质（酶 活性）。 这将 区分不相关的多态性与实际的活性改变 突变。5)为了确定SRD 5A 2基因与 通过基因分型[使用相关序列变异]的前列腺癌 在（4）中鉴定的] SRD 5A 2基因在三个种族-民族组中[亚洲人- 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]的前列腺癌病例和匹配的对照。6)到 利用（5）中确定的关联的强度来利用结果 以及这些等位基因在三个种族-民族群体中的流行率， 估计SRD 5A 2基因型在解释变异中的贡献 在这三组男性中， 前列腺癌的风险不同。7)为了进一步表征 SRD 5A 2基因在前列腺癌中的作用 这个基因的突变。

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.