5ALPHA REDUCTASE GENOTYPE, RACE AND PROSTATE CANCER RISK

5α 还原酶基因型、种族和前列腺癌风险

基本信息

批准号：
2458206
负责人：
JUERGEN K REICHARDT
金额：
$ 43.55万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 1999-07-31
项目状态：
已结题

项目摘要

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.

在美国，每年有近 200,000 名男性被诊断出前列腺癌每年约有 38,000 人死亡。在这个应用程序中，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很大程度上受以下因素影响人类 II 型 5α 还原酶 (SRD5A2) 基因中的特定基因型。我们建议用分子研究以下七个具体目标遗传和流行病学工具： 1) 确定之间的关系通过对特定多态性进行基因分型来研究 SRD5A2 基因和前列腺癌男性 SRD5A2 基因中的 DNA 标记 [TA 短串联重复序列 (TA-STR)] 患有前列腺癌的人以及来自非洲裔美国人和白人的匹配对照男性患前列腺癌的风险差异很大。 2) 表征DNA 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 进行测序来发现癌症携带高风险 SRD5A2 基因型的前列腺癌男性在（1）中鉴定，从而确定种系的精确性质 DNA 改变易诱发前列腺癌。 3) 表征DNA SRD5A2 基因的序列变异可能会保护亚洲男性免受通过对少量正常人（对照）的 DNA 进行测序来检测前列腺癌亚洲男性的二氢睾酮 (DHT) 水平较低，因此确定可能具有保护作用的种系 DNA 改变前列腺癌。 4) 生化性质测定（酶 (2) 和 (3) 中确定的每个序列变异的活性）。这将区分不相关的多态性和实际的活性改变突变。 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)]中鉴定出三个种族群体中的SRD5A2基因[亚洲- 美国人（此处定义为华裔美国人和日裔美国人）、非裔美国人美国人和白人]前列腺癌病例和匹配对照。 6) 到根据 (5) 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群体中的流行率估计 SRD5A2 基因型在解释变异中的贡献这三组男性的前列腺癌风险普遍较高前列腺癌的风险不同。 7) 进一步表征通过定义体细胞来研究SRD5A2基因与前列腺癌的关系该基因发生突变。