Integrating Genomics and Metabolomics to Develop Predictive Models of Prostate Cancer in Multiethnic Men

整合基因组学和代谢组学来开发多种族男性前列腺癌的预测模型

• 批准号: 10768434
• 负责人: Burcu Frances Darst
• 金额: $ 8.8万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10768434
• 关键词: African American; African ancestry; American; Award; Biological; Cancer Etiology; Cessation of life; European; Funding; Genetic; Genetic Risk; Genomics; Goals; Incidence; Individual; Indolent; Investigation; Malignant neoplasm of prostate; Measures; Mediating; Mendelian randomization; Metabolic; Modeling; Parents; Phase; Population; Predictive Value; Preventive measure; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Research; Sampling; Screening for Prostate Cancer; Subgroup; Techniques; Training; anticancer research; cohort; genome wide association study; health disparity; high risk population; improved; men; metabolomics; mortality; multi-ethnic; novel; polygenic risk score; predictive modeling; prostate cancer model; prostate cancer risk; risk variant; screening; statistics

PROJECT SUMMARY/ABSTRACT OF THE FUNDED PARENT AWARD Prostate cancer (PCa) is the second leading cause of cancer death among American men, with men of African ancestry have the highest PCa incidence and mortality rates. While the causes of this notable health disparity are not fully understood, growing evidence suggests that genetics is a contributing factor. However, most PCa research has focused on men of European descent, particularly genome-wide association studies (GWAS), which has resulted in polygenic models having poorer predictive value in non-Europeans. The overarching goal of this research is to identify genomic and metabolomic factors that contribute to PCa risk in men across multi- ancestry populations. In the R00 phase of this award, Dr. Darst will initiate a new line of research that applies integrative techniques to investigate combined genomic and metabolomic factors influencing PCa risk. This will build directly upon the research and training received in the K99 period. She will identify genetically regulated metabolites that could be causally associated with PCa risk in multi-ancestry populations and/or indicate potentially novel genetic risk loci (Aim 1). This will require developing a large multi-ancestry metabolomic imputation panel and performing two-sample Mendelian randomization for each metabolite and GWAS summary statistics from the large and diverse PRACTICAL Consortium. Using a subset of 872 African American men from the Multiethnic Cohort (MEC) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Dr. Darst will investigate the biological mechanisms implicated by genetic risk of PCa, as measured by a multi- ancestry polygenic risk score, metabolites that could mediate the effects of genetic factors on overall and aggressive PCa, and whether integrative techniques could be used to identify genomic and metabolomic factors that distinguish subgroups of individuals with high PCa risk (Aim 2). Results are expected to substantially improve our ability to detect high risk individuals who would benefit from earlier or more intensive PCa screening across multi-ancestry populations and provide novel biological mechanisms to target for preventative measures, likely reducing PCa mortality and the number of indolent PCa cases treated unnecessarily.

受资助父母奖的项目摘要/摘要 前列腺癌(PCA)是美国男性癌症死亡的第二大原因，与非洲男性一样 血统的前列腺癌发病率和死亡率最高。虽然造成这种显著健康差距的原因 尽管还没有完全了解，但越来越多的证据表明，遗传是一个促成因素。然而，大多数PCA 研究的重点是欧洲血统的男性，特别是全基因组关联研究(GWAS)， 这导致多基因模型在非欧洲人中的预测价值较差。首要目标是 这项研究的目的是确定导致男性前列腺癌风险的基因组和代谢因素。 祖先种群。在该奖项的R00阶段，达斯特博士将启动一项适用于 综合技术研究影响前列腺癌风险的基因组和代谢综合因素。这将是 直接建立在K99期间所接受的研究和培训的基础上。她将识别受基因控制的 在多血统人群中可能与前列腺癌风险相关的代谢物和/或指示 潜在的新遗传风险基因座(目标1)。这将需要开发一个大型的多祖先代谢体 归罪小组，并对每个代谢物和GWAS摘要执行两样本孟德尔随机化 来自大型和多样化的实践联盟的统计数据。使用来自872名非洲裔美国人的子集 多种族队列(MEC)和前列腺癌、肺癌、结直肠癌和卵巢癌(PLCO)筛查试验， 达斯特博士将研究前列腺癌的遗传风险所涉及的生物学机制，如通过多项 祖先多基因风险评分，代谢物可以中介遗传因素对总体和 侵袭性主成分分析，以及整合技术是否可用于识别基因组和代谢因子 区分前列腺癌风险较高的个体亚群(目标2)。预计业绩将大幅改善 我们能够发现将从更早或更密集的PCA筛查中受益的高危个体 并提供新的生物机制，以针对预防措施，可能 降低PCa死亡率和不必要治疗的惰性PCa病例数量。