Molecular Epidemiology of Prostate Cancer in Tobagonians

与白种人相比，非裔美国人患前列腺癌的风险更高，这是众所周知的，但对导致这种高风险的因素知之甚少。在我们的多巴哥前列腺调查中，我们记录了在多巴哥岛上的加勒比非洲裔人口中，50-79岁的多巴哥男性中前列腺癌的发病率非常高，为16%。我们发现了可能导致该人群前列腺癌风险过高的三个风险域：1)骨矿物质密度评估的有丝分裂因子（如性类固醇激素、生长因子）的高累积暴露指标；2)宿主易感性（性类固醇激素和白细胞介素6信号相关基因的分子变异）；3)感染人类疱疹病毒8 (HHV8)（很可能是慢性感染）。此外，我们的研究表明，这些风险域之间的相互作用在生物学上是合理的。具体的目标。1. 继续筛查，将病例控制系列增加到550例，1100例非病例。2. 评估加勒比黑人男性中主要激素信号基因的分子变异与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各自独立与前列腺癌风险相关的假设，并验证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，非裔美国人与多巴哥人群中观察到的高危性激素相关基因型相同。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的关联，并进一步定义性激素相关的遗传易感性，将确定一个高风险群体，可能需要开发干预措施，如激素调节、HHV8疫苗或抗病毒治疗，这可以降低非洲-加勒比人、非洲裔美国人和其他人群患前列腺癌的风险。

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.