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科恶性肿瘤，居第二位。 美国男性癌症死亡原因。前列腺中的雄激素途径 被认为通过刺激细胞增殖来促进癌症的发生， 从而增加了随机遗传错误累积和 会导致恶性表型。前列腺中的雄激素活性是 由高度编码的酶和转录因子调节 多态基因。我们建议检验这样一个假设，即拥有 雄激素途径基因中的某些变异等位基因会增加男性的 患前列腺癌的风险。具体来说，感兴趣的基因编码：(1) 类固醇5α-还原酶II(SRD5A2)，它在体内激活雄激素 前列腺；(2)雄激素受体(AR)，一种雄激素依赖的核 转录因子；(3)前列腺特异性抗原(PSA)，一种丝氨酸 被AR反式激活的蛋白酶，切割并逆转生长抑制 胰岛素样生长因子结合蛋白-3的作用。SRDSA2， AR和PSA基因各自编码的产物介导雄激素刺激 前列腺。此外，每个基因都有一个多态， 已证明的功能和足够的等位基因频率来解释 前列腺癌在美国人口中占有相当大的比例。 我们建议进行一项心血管疾病的嵌套病例对照研究。 健康研究(CHS)，以检验拥有变异等位基因的假设 在SRDSA2、AR和PSA基因中，单独和组合增加 男性患前列腺癌的风险。CHS是一项针对老年人的多中心队列研究 预期收集详细访谈数据和血液的成年人 自1989年以来的样本。病例将是大约210名社区卫生服务男性参与者 在注册后和1999年被诊断出患有前列腺癌。控制 将有420名CHS男性参与者，按年龄和种族与病例频率匹配， 在1999年之前没有被诊断出患有前列腺癌，并且活着的人 匹配病例的诊断日期。我们建议进行实验室 对CHS提供的DNA样本进行分析以确定是否存在变异 病例和对照的等位基因，并进行统计分析，以评估 SRD5A2、AR和PSA基因型影响患前列腺癌的风险。这个 前列腺癌高危基因图谱的鉴定与确认 癌症可以实现更好的筛查和潜在的预防性干预 针对的是基因产物。

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.