Androgen Pathway and Genetic Risk of Prostate Cancer

描述（由申请人提供）： 前列腺癌是最常见的内部恶性肿瘤和第二大 美国男性癌症死亡率的原因。前列腺中的雄激素通路 被认为通过刺激细胞增殖介导致癌作用， 从而增加了随机遗传错误累积的机会， 产生恶性表型。前列腺中的雄激素活性 由酶和转录因子调节，这些酶和转录因子由高度 多态基因我们建议测试的假设，拥有 雄激素途径基因中的某些变异等位基因增加了男性的 患前列腺癌的风险。具体地，感兴趣的基因编码：（1） 类固醇5 α-还原酶II型（SRD 5A 2），其生物激活 前列腺;（2）雄激素受体（AR），一种雄激素依赖性核 （3）前列腺特异性抗原（PSA），一种丝氨酸 由AR反式激活的蛋白酶，切割并逆转生长抑制因子 胰岛素样生长因子结合蛋白-3（IGFBP-3）的作用。SRDSA2， AR和PSA基因各自编码介导雄激素刺激的产物， 前列腺此外，每个基因都具有多态性， 证明了功能性和足够的等位基因频率来解释 前列腺癌在美国人口中占很大比例。 我们建议在心血管系统内进行一项巢式病例对照研究。 健康研究（CHS），以检验拥有变异等位基因的假设， 在SRDSA 2、AR和PSA基因中，单独或组合， 男性患前列腺癌的风险。CHS是一项在老年人中进行的多中心队列研究。 已前瞻性收集详细访谈数据和血液的成年人 1989年以来的样品。病例将涉及约210名CHS男性受试者 在入组后和1999年被诊断为前列腺癌。控制 将有420名CHS男性参与者，频率与年龄和种族的病例相匹配， 在1999年之前没有被诊断出患有前列腺癌， 匹配病例的诊断日期。我们建议进行实验室 分析CHS提供的DNA样本，以确定是否存在变异 病例和对照之间的等位基因，并进行统计分析，以评估是否 SRD 5A 2、AR和PSA基因型影响前列腺癌风险的 前列腺高风险基因谱鉴定和确认 癌症可以使更好的筛查和潜在的预防干预成为可能 针对基因产物。

DESCRIPTION (provided by applicant): Prostate cancer is the most common internal malignancy and second leading cause of cancer mortality among U.S. men. The androgen pathway in the prostate is believed to mediate carcinogenesis by stimulating cell proliferation, thereby increasing the opportunity for random genetic errors to accumulate and give rise to a malignant phenotype. Androgen activity in the prostate is regulated by enzymes and transcription factors that are encoded by highly polymorphic genes. We propose to test the hypothesis that the possession of certain variant alleles in genes in the androgen pathway increases a man's risk of prostate cancer. Specifically the genes of interest encode: (1) steroid 5 alpha-reductase type II (SRD5A2), which bioactivates androgens in the prostate; (2) androgen receptor (AR), an androgen-dependent nuclear transcription factor; and (3) prostate-specific antigen (PSA), a serine protease transactivated by AR that cleaves and reverses the growth-inhibitory effects of insulin-like growth factor binding protein-3 (IGFBP-3). The SRDSA2, AR, and PSA genes each encode products that mediate androgen stimulation of the prostate. Furthermore, each gene possesses a polymorphism with demonstrated functionality and sufficient allelic frequency to explain a substantial proportion of prostate cancer in the U.S. population. We propose to conduct a nested case-control study within the Cardiovascular Health Study (CHS) to test the hypothesis that possession of variant alleles in the SRDSA2, AR, and PSA genes, individually and in combination, increases a man's risk of prostate cancer. CHS is a multicenter cohort study in older adults that has prospectively collected detailed interview data and blood samples since 1989. Cases will be approximately 210 CHS male participants diagnosed with prostate cancer after enrollment and through 1999. Controls will be 420 CHS male participants, frequency matched to cases by age and race, who were not diagnosed with prostate cancer through 1999 and who were alive as of the date of diagnosis of the matched case. We propose to conduct laboratory analysis of DNA samples provided by CHS to determine the presence of variant alleles among cases and controls, and statistical analysis to assess whether SRD5A2, AR, and PSA genotypes influence the risk of prostate cancer. The identification and confirmation of high-risk genetic profiles for prostate cancer could enable better screening and potential preventive interventions aimed at the gene products.