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: 10647719
• 负责人: Chong Wu
• 金额: $ 66.25万
• 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/10647719
• 关键词: Address; African; African ancestry; Area; Assessment tool; 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; European ancestry; Freezing; Gene Expression; Genes; Genetic; Growth; Hematopoietic Neoplasms; Histologic; Incidence; Invaded; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Methodology; Methods; Methylation; Modeling; Other Genetics; Outcome; Patients; Performance; Predictive Cancer Model; Prospective cohort; Prostate; Proteins; Reduce health disparities; Regulator Genes; Reporting; Research Design; Research Support; Risk; Risk Factors; Role; Screening for Prostate Cancer; Selection Bias; Series; Statistical Methods; Testing; Tissues; Validation; Work; biomarker identification; candidate identification; candidate marker; design; epidemiologic data; epidemiology study; genetic predictors; high risk population; improved; innovation; lifestyle factors; men; model building; mortality; multiple omics; non-genetic; novel; predictive modeling; programs; prostate cancer risk; protein biomarkers; protein expression; racial population; 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) 是男性第二常见的恶性肿瘤， 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 大约 10-15% 的被诊断患有侵袭性 PCa 的患者中发生了 PCa。 PCa 的病因尚不清楚。基础研究支持某些蛋白质的关键作用 在 PCa 开发中。流行病学研究还发现了多种候选蛋白 PCa 的生物标志物。然而，传统的流行病学研究主要在 欧洲人，目前尚不清楚哪些候选蛋白质生物标志物可能是欧洲特有的 或泛种族。此外，许多这些生物标志物的研究结果并不一致，可能 由于主要的方法学限制，例如选择偏差和不受控制的混杂因素。 除了了解病因之外，识别因果蛋白质生物标志物可能有助于 改善风险预测。对于 PCa，已做出大量努力来识别高风险 改善 PCa 筛查的人群。然而，可用 PCa 风险的表现 预测模型仍然不能令人满意。迫切需要 1) 应用新颖的研究设计 减少了表征 PCa 因果关系的传统生物标志物研究的局限性 非洲人和欧洲人的蛋白质生物标志物，以提高对病因的了解；和 2) 开发改进的预测模型，可以有效促进 PCa 风险/攻击性 对非洲人和欧洲人的评估。一种可能减少限制的策略 不可测量的混杂是使用遗传工具来评估之间的关系 蛋白质和前列腺癌。虽然我们之前的研究利用了血液中测量的蛋白质，但它也 前列腺组织是前列腺癌发展最相关的组织，对于研究前列腺组织至关重要，因为许多 蛋白质显示出组织特异性效应。拟议的项目将应用一系列新的研究 解决这些重要的知识差距。具体来说，我们将 1) 进行一项研究以确定 非洲人和前列腺癌风险和攻击性的推定因果蛋白质生物标志物 欧洲人应用新颖的方法（目标 1）； 2) 对顶级蛋白质生物标志物进行功能表征 表彰其在 PCa 生物学中的作用（目标 2）； 3) 制定并验证特定种族和泛种族的 通过纳入新确定的候选者，预测 PCa 风险和侵袭性的模型 蛋白质生物标志物和多种统计方法的整合结果（目标 3）。我们的研究将 生成有关 PCa 病因学的重要新知识，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 方法也可以应用于其他复杂疾病。

项目成果

Regional analysis to delineate intrasample heterogeneity with RegionalST.

使用 RegionalST 描述样本内异质性的区域分析。

• 发表时间: 2024-03-29
• 作者: Lyu, Yue;Wu, Chong;Sun, Wei;Li, Ziyi
• 通讯作者: Li, Ziyi