Obesity and prostate cancer risk in Black and White men: a functional approach

描述（由申请人提供）：肥胖（身体质量指数（BMI）e30）和前列腺癌（PCa）构成了重大的公共卫生问题，在非洲裔美国男性（AAM）和非西班牙裔欧洲男性（EAM）之间存在持续的差异。肥胖作为一种生理状态，其特点是个体荷尔蒙水平的显著改变。由于前列腺癌是一种激素疾病，从生物学角度来看，肥胖影响前列腺癌的风险似乎是合理的，可能是通过激素失衡导致肿瘤生长的改变。这种影响在AAM中可能更为明显，因为他们的PCa肿瘤在基线时往往表现出更具侵略性的生物学行为。事实上，一些研究已经将肥胖与AAM中更具侵略性的PCa联系起来，这表明肥胖与PCa差异有关。然而，迄今为止，旨在阐明肥胖对AAM和EAM中PCa风险影响的机制生物学研究尚缺乏。与已发表的文献一致，我们最近的初步数据表明，肥胖可能是AAM的PCa风险因素，风险程度取决于个体的遗传变异。我们项目的目标是了解种系遗传变异的共同影响

DESCRIPTION (provided by applicant): Both obesity (Body Mass Index (BMI)e30) and prostate cancer (PCa) constitute significant public health problems, for which there are persistent disparities between African American men (AAM) and Non-Hispanic European men (EAM). Obesity as a physiological state is characterized by significant alterations in the individual's hormonal profile. Since PCa is a hormonal disease, it appears biologically plausible that obesity affects PCa risk, possibly through the altered tumor growth enabled by the hormonal imbalances. This effect may be even more pronounced in AAM since their PCa tumors tend to demonstrate more aggressive biological behavior at baseline. Indeed, a few studies have linked obesity to more aggressive PCa in AAM specifically, suggesting involvement of obesity in PCa disparity. However, to date, the mechanistic biology studies aimed to elucidate the effects of obesity on PCa risk in AAM and EAM are lacking. In concordance with the published literature, our recent preliminary data suggest that obesity may be a PCa risk factor in AAM, and the extent of risk is determined by the individual's genetic variation. The goal of our project is to understand the joint impact of germline genetic variations and obesity on prostate tumor biology and PCa risk in AAM and EAM. We hypothesize that select genetic variation, when combined with the environment of obesity, influences PCa risk by impacting key cellular processes relevant to the tumor biology. To test this hypothesis, a functional integrated approach is proposed, that utilizes prostate tumor biology as a starting point. In the Aim 1, we will investigate whether there are differences in the gene expression profiles in prostate tumors and healthy prostate tissue of obese and non-obese men in each race. In the Aim 2, we will test the functional significance of the identified genes. Finally, in te Aim 3 we propose to link obtained data to PCa risk through variation in the germline genome. Significance. Understanding the specific role of obesity in PCa risk is crucial for efficient development of individualized PCa risk estimation in AAM and EAM; selection of the most appropriate treatment modalities; estimating the risk of progression; advancing knowledge of the tumor biology in AAM and EAM; and developing targeted risk reduction interventions. Innovation. Our work is innovative, comprehensive and contemporary in that we propose functionally relevant genetic variation to be incorporated in the risk prediction. Future direction. Guided by our findings, we plan to launch a clinical preventive study aimed to validate the results in a larger cohort of AAM and EAM, improve the proposed approach, and test the chemopreventive and/or lifestyle interventions targeted towards specific tumor and genetic features in AAM and EAM. In addition, our proposed model can be applied to study gene-environmental interactions in virtually any other malignancy.