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）是男性中第二常见的恶性肿瘤，患有 非洲人和欧洲人的发病率和死亡率各不相同。绝大多数死亡 在大约10-15％的被诊断为攻击性PCA的患者中，PCA发生。 PCA的病因知之甚少。基础研究支持某些蛋白质的关键作用 在PCA开发中。流行病学研究还确定了多种候选蛋白 PCA的生物标志物。但是，传统的流行病学研究主要是在 欧洲人，目前尚不清楚哪种候选蛋白质生物标志物可能是欧洲特定的 或泛民族。此外，许多此类生物标志物的发现是不一致的，可能 由于主要的方法论上的局限性，例如选择偏差和不受控制的混杂。 除了了解病因外，识别因果蛋白生物标志物还可以潜在地贡献 改善风险预测。对于PCA，已经做出了巨大的努力来识别高风险 改善PCA筛查的种群。但是，可用PCA风险的性能 预测模型仍然不令人满意。有关键的需要1）应用新颖的研究设计 随着传统生物标志物研究的限制，用于表征PCA因果关系 跨非洲人和欧洲人的蛋白质生物标志物，以提高病因学的理解；和2） 开发改进的预测模型，可能有效地促进PCA风险/侵略性 非洲人和欧洲人的评估。一种可能降低限制的策略 无法衡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，但也是 研究前列腺组织，这是PCA发育中最相关的组织，作为许多水平 蛋白质显示组织特异性作用。拟议的项目将应用一系列新研究 解决这些重要的知识差距。具体来说，我们将1）进行研究以识别 推定的因果蛋白生物标志物，用于PCA风险和侵略性的非洲人和侵略性 欧洲人通过应用新颖的方法（AIM 1）； 2）功能表征顶级蛋白质生物标志物 因为它们在PCA生物学中的作用（AIM 2）； 3）发展和验证种族特异性和泛种族 通过合并新确定的候选人，PCA风险和侵略性的预测模型 蛋白质生物标志物和通过多种统计方法的结果整合（AIM 3）。我们的研究愿意 为PCA病因生成重要的新知识，并发展了改进的PCA 非洲人和欧洲人的风险/侵略性预测模型。拟议的新 方法也可以应用于其他复杂疾病。