Molecular Epidemiology of Prostate Cancer in Tobagonians

描述(由申请人提供)：与高加索美国人相比，非裔美国人患前列腺癌的风险更高，但对导致这一高风险的因素知之甚少。在我们的多巴哥前列腺癌调查中，我们记录了多巴哥岛上的非洲裔加勒比人口中前列腺癌的发病率非常高，50-79岁的多巴哥男性中有16%。我们发现了三个可能导致前列腺癌风险过高的风险领域：1)骨密度评估的高累积暴露于有丝分裂因子(如性类固醇激素、生长因子)的指标；2)宿主易感性(与性类固醇激素和白细胞介素6信号相关的基因的分子变异)；3)人类疱疹病毒8型(HHV8)感染(最有可能是慢性感染)。此外，我们的研究表明，这些风险领域之间存在生物学上合理的相互作用。明确的目标。1.继续筛查，病例对照系列增至550例，非病例1100例。2.探讨主要激素信号转导基因分子变异与非洲裔加勒比男性前列腺癌易感性的关系。3.验证HHV8暴露和激素信号基因的分子变异分别与前列腺癌风险独立相关的假设，并检验这些因素之间的相互作用是风险的主要决定因素的假设。来自其他研究的数据表明，非洲裔美国人拥有在多巴哥人口中观察到的与性激素相关的高危型。HHV8血清阳性在美国人群中并不罕见。确认HHV8感染与前列腺癌风险之间的关联，以及进一步定义与性激素相关的遗传易感性，将确定可能需要开发干预措施的高危群体，如激素调节、HHV8疫苗或抗病毒治疗，这些干预措施可能会降低非裔加勒比人、非裔美国人和其他人群患前列腺癌的风险。

DESCRIPTION (provided by applicant): Higher prostate cancer risk is well established in African Americans compared with Caucasian Americans, but little is known about factors contributing to this high risk. In our Tobago Prostate Survey, we have documented an extraordinarily high rate of prostate cancer, 16% among Tobago men aged 50-79, in the Afro-Caribbean population on the island of Tobago. We have discovered three risk domains which may contribute to the excess prostate cancer risk in this population: 1) indicators of high cumulative exposure to mitogenic factors (e.g., sex steroid hormones, growth factors) as assessed by bone mineral density; 2) host susceptibility (molecular variation in genes related to sex steroid hormone and interleukin 6 signaling); and 3) infection (most likely chronic) with human herpes virus 8 (HHV8). Moreover, our studies suggest biologically plausible interactions among these risk domains. Specific aims. 1. Continue screening to increase the case control series to 550 cases, 1100 non-cases. 2. To evaluate the association of molecular variation in major hormonal signaling genes and susceptibility to prostate cancer among Afro-Caribbean men. 3. To test the hypotheses that HHV8 exposure and molecular variation in the hormonal signaling genes are each independently related to prostate cancer risk, and test the hypothesis that interactions among these factors are a major determinant of risk. Data from other studies suggest that African Americans share the high risk sex hormone related genotypes observed in the Tobago population. HHV8 seropositivity is not rare in the US population. Confirmation of the association of HHV8 infection with prostate cancer risk, and further definition of sex hormone related genetic susceptibility, will identify a high risk group which may warrant development of interventions, such as hormone modulation, or HHV8 vaccine or anti-viral therapy, which could reduce risk for prostate cancer among Afro-Caribbeans, African Americans and other populations.