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

黑人和白人的肥胖和前列腺癌风险：功能性方法

• 批准号: 8773914
• 负责人: Ganna Chornokur
• 金额: $ 21.99万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773914
• 关键词: Affect; African; African American; Aftercare; Age; Alleles; Behavior; Biochemical; Biological; Biological Assay; Biology; Body mass index; Cancer Burden; Cell physiology; Chemopreventive Agent; Clinical; DNA; Data; Development; Diagnosis; Diet; Disease; Environment; Epidemiologic Studies; Etiology; European; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genotype; Gleason Grade for Prostate Cancer; Goals; Growth; Hormonal; Incidence; Individual; Intervention; Investigation; Joints; Kidney; Knowledge; Life Style; Link; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Minor; Mission; Modality; Modeling; Molecular Profiling; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Obesity; Odds Ratio; PC3 cell line; Pancreas; Pathway interactions; Physiological; Policies; Population Heterogeneity; Preventive; Prostate; Prostatic Neoplasms; Public Health; Publishing; Race; Recurrence; Research; Research Support; Risk; Risk Estimate; Risk Factors; Risk Reduction; Role; Serum; Single Nucleotide Polymorphism; Societies; Testing; Tissues; Tumor Biology; Tumor-Derived; Variant; Work; cancer health disparity; cancer prevention; cancer risk; case control; cohort; genome wide association study; improved; innovation; interest; knock-down; lifestyle intervention; member; men; nano-string; prostate cancer prevention; public health relevance; transcription factor; tumor; tumor growth

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.

描述（由申请人提供）：肥胖（体重指数（BMI）e30）和前列腺癌（PCa）均构成严重的公共卫生问题，在非洲裔美国男性（AAM）和非西班牙裔欧洲男性（EAM）之间存在持续差异。肥胖作为一种生理状态，其特征在于个体激素谱的显著改变。由于前列腺癌是一种激素性疾病，从生物学上看，肥胖影响前列腺癌风险似乎是合理的，可能是通过激素失衡改变肿瘤生长。这种效应在AAM中可能更加明显，因为他们的PCa肿瘤倾向于在基线时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中更积极的PCa联系起来，这表明肥胖参与了PCa差异。然而，到目前为止，机制生物学研究，旨在阐明的影响，肥胖对PCa风险的AAM和EAM是缺乏的。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中PCa的危险因素，并且风险程度由个体的遗传变异决定。我们项目的目标是了解生殖系遗传变异的共同影响 和肥胖对AAM和EAM中前列腺肿瘤生物学和PCa风险的影响。我们假设，选择遗传变异，结合肥胖的环境，影响PCa的风险，通过影响关键的细胞过程相关的肿瘤生物学。为了验证这一假设，提出了一种功能整合的方法，利用前列腺肿瘤生物学作为出发点。在目标1中，我们将研究每个种族中肥胖和非肥胖男性的前列腺肿瘤和健康前列腺组织中的基因表达谱是否存在差异。在目标2中，我们将测试所识别基因的功能意义。最后，在目的3中，我们建议通过种系基因组的变异将获得的数据与PCa风险联系起来。意义了解肥胖在PCa风险中的具体作用对于有效开发AAM和EAM中的个体化PCa风险评估至关重要;选择最合适的治疗方式;估计进展风险;提高AAM和EAM中肿瘤生物学的知识;以及制定有针对性的风险降低干预措施。创新我们的工作是创新的，全面的和当代的，因为我们提出了功能相关的遗传变异纳入风险预测。未来的方向。在我们的研究结果的指导下，我们计划开展一项临床预防性研究，旨在验证更大的AAM和EAM队列的结果，改进所提出的方法，并测试针对AAM和EAM中特定肿瘤和遗传特征的化学预防和/或生活方式干预措施。此外，我们提出的模型可以应用于研究几乎任何其他恶性肿瘤的基因-环境相互作用。