Uncovering causal protein markers to improve prostate cancer etiology understanding and risk prediction in Africans and Europeans

发现因果蛋白标记物以提高非洲人和欧洲人对前列腺癌病因的了解和风险预测

• 批准号: 10446594
• 负责人: Chong Wu
• 金额: $ 77.08万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446594
• 关键词: Address; African; Area; Basic Science; Biological; Biological Assay; Biological Markers; Blood; Brain; Cancer Biology; Cancer Etiology; Cell Line; Cessation of life; Clinical; Complex; DNA Methylation; Data; Derivation procedure; Development; Diagnosis; Dietary Factors; Disease; Ethnic Origin; Etiology; European; Freezing; Gene Expression; Genes; Genetic; Growth; Hematopoietic Neoplasms; Histologic; Incidence; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Methodology; Methods; Methylation; Modeling; Other Genetics; Outcome; Patients; Performance; Prospective cohort; Prostate; Proteins; Race; Reduce health disparities; Regulator Genes; Reporting; Research Design; Research Support; Risk; Role; Screening for Prostate Cancer; Selection Bias; Series; Statistical Methods; Testing; Tissues; Validation; Work; base; candidate marker; case control; design; epidemiologic data; epidemiology study; high risk population; improved; innovation; instrument; lifestyle factors; men; model building; mortality; multiple omics; non-genetic; novel; predictive modeling; programs; prostate cancer risk; protein biomarkers; protein expression; risk prediction; risk prediction model; screening; transcriptome

Prostate cancer (PCa) is the second most commonly diagnosed malignancy in men, with incidence and mortality rates varying across Africans and Europeans. The vast majority of deaths from PCa occur among the approximately 10-15% of patients diagnosed with aggressive PCa. The etiology of PCa is poorly understood. Basic research supports a crucial role of certain proteins in PCa development. Epidemiological studies also have identified multiple candidate protein biomarkers for PCa. However, conventional epidemiologic studies were conducted primarily in Europeans, and it is unclear which of the candidate protein biomarkers may be European-specific or pan-ethnic. Also, findings with many of these biomarkers have been inconsistent, potentially due to major methodological limitations, such as selection bias and uncontrolled confounding. Besides understanding etiology, identifying causal protein biomarkers can potentially contribute to improving risk prediction. For PCa, substantial efforts have been made to identify high-risk populations for improving PCa screening. However, the performance of available PCa risk prediction models remains unsatisfactory. There are critical needs to 1) apply a novel study design with reduced limitations of conventional biomarker studies for characterizing PCa causally related protein biomarkers across Africans and Europeans to improve the etiology understanding; and 2) develop improved prediction models that may effectively facilitate PCa risk/aggressiveness assessment across Africans and Europeans. One strategy to potentially decrease limitations of unmeasured confounding is to use genetic instruments for assessing the relationship between proteins and PCa. While our previous studies have utilized proteins measured in blood, it is also critical to study prostate tissue, the most relevant tissue for PCa development, as levels of many proteins show tissue-specific effects. The proposed project will apply a series of new studies to address these important knowledge gaps. Specifically, we will 1) conduct a study to identify putative causal protein biomarkers for PCa risk and aggressiveness across Africans and Europeans by applying novel methods (Aim 1); 2) functionally characterize top protein biomarkers for their roles in PCa biology (Aim 2); and 3) develop and validate ethnic-specific and pan-ethnic prediction models for PCa risk and aggressiveness, by incorporating newly identified candidate protein biomarkers and integrating results from multiple statistical methods (Aim 3). Our study will generate important new knowledge for PCa etiology, and develop improved PCa risk/aggressiveness prediction models across Africans and Europeans. The proposed new methods can also be applied to other complex diseases.

前列腺癌（PCa）是男性中第二大最常见的恶性肿瘤， 发病率和死亡率在非洲和欧洲各不相同。绝大多数的死亡 在诊断为侵袭性PCa的患者中，约10-15%的患者发生了前列腺癌。 PCa的病因学知之甚少。基础研究支持某些蛋白质的关键作用 在PCa的发展。流行病学研究还鉴定了多种候选蛋白质 PCa的生物标志物。然而，传统的流行病学研究主要是在 欧洲人，目前还不清楚哪些候选蛋白质生物标志物可能是欧洲特异性的 或泛种族。此外，这些生物标志物中的许多发现不一致，可能 由于主要的方法学限制，如选择偏倚和不受控制的混杂。 除了了解病因，确定致病蛋白质生物标志物可能有助于 改善风险预测。对于PCa，已经做出了大量努力来识别高风险 用于改善PCa筛查的人群。然而，可用PCa风险的性能 预测模型仍然不能令人满意。关键需要：1）采用新的研究设计 减少了传统生物标志物研究对表征PCa因果相关性的限制 非洲人和欧洲人的蛋白质生物标志物，以提高对病因学的理解; 2） 开发改进的预测模型，可以有效地促进PCa风险/侵略性 非洲人和欧洲人之间的评估。一种潜在地减少 不可测量的混杂是使用遗传工具来评估 蛋白质和PCa。虽然我们以前的研究利用了血液中测量的蛋白质， 对于研究前列腺组织至关重要，前列腺组织是与PCa发展最相关的组织，因为许多前列腺组织的水平， 蛋白质显示组织特异性作用。拟议的项目将采用一系列新的研究， 填补这些重要的知识空白。具体而言，我们将：1）进行研究， 非洲人中PCa风险和侵略性的假定致病蛋白质生物标志物， 欧洲人通过应用新的方法（目的1）; 2）功能表征顶级蛋白质生物标志物 在PCa生物学中的作用（目标2）; 3）开发和验证种族特异性和泛种族 预测模型PCa的风险和侵略性，通过纳入新确定的候选 蛋白质生物标志物和整合来自多种统计方法的结果（目的3）。我们的研究将 为PCa病因学提供重要的新知识，并开发改进的PCa 非洲人和欧洲人的风险/攻击性预测模型。拟议的新 这些方法也可以应用于其他复杂疾病。