Precision Prostate Cancer Screening with Genetically Adjusted Prostate-Specific Antigen Levels

通过基因调整前列腺特异性抗原水平进行精准前列腺癌筛查

• 批准号: 10378651
• 负责人: John S. Witte
• 金额: $ 57.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378651
• 关键词: Accounting; Advisory Committees; Affect; African ancestry; Antigenic Variation; Asian ancestry; Bayesian Method; Biochemical; Cessation of life; Characteristics; Clinical; Complex; Data; Diagnosis; Disease; European; Failure; Genes; Genetic; Genetic Risk; Genetic study; Goals; Heritability; Individual; Joints; Latino; Life Cycle Stages; Light; Malignant neoplasm of prostate; Maps; Measures; Mediation; Modeling; Morbidity - disease rate; Nature; Neoplasm Metastasis; Outcome; PSA level; PSA screening; Patients; Periodicity; Physicians; Polygenic Traits; Population; Predisposing Factor; Preventive service; Prostate-Specific Antigen; Research; Resources; Risk; Risk Factors; Sampling; Screening for Prostate Cancer; Sum; Testing; Time; Translations; United States; Unnecessary Procedures; Variant; Work; aged; base; clinical decision-making; genetic information; genetic variant; genome wide association study; genome-wide; improved; man; men; mortality; non-genetic; novel; overtreatment; polygenic risk score; predictive modeling; prevent; prostate biopsy; prostate cancer model; prostate cancer prevention; prostate cancer risk; risk variant; screening; transcriptome

ABSTRACT The United States Preventive Services Task Force (USPSTF) recently graded the use of prostate-specific antigen (PSA) to screen for prostate cancer (PCa) a “C”: “For men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician.” The USPSTF decided that PSA screening as it currently exists is inadequate for widespread implementation. It is thus important to ask the question how PSA screening can be improved to reduce overdiagnosis, overtreatment, and PCa mortality. Evidence suggests that the incorporation of genetic factors into PSA screening decisions could do just that. PSA levels have been shown to be highly heritable, but the associated genetic variants that have been identified thus far explain only some of the variation. Moreover, the variation explained is even smaller when dealing with non-European populations. If we can determine the genetic factors that predispose individuals to high PSA levels independently of PCa, we could then account for them as part of a new PSA screening paradigm. We propose to do just this with a large-scale project combining data from 17 studies of men both with and without PCa, all of whom have data on both PSA levels and genome-wide variants. In sum, the studies consist of 653,076 men, including 106,326 men of African ancestry, 35,683 of Latino ancestry, and 10,001 of Asian ancestry. In Aim 1, we will undertake a multi-ancestry genome-wide association study (GWAS) of PSA levels that is 20-times larger than any previous such analysis, as well as the first ever transcriptome- wide association study (TWAS) of PSA levels. We will then leverage the multi-ancestry nature of our sample to discover additional genetic variants associated with PSA via fine mapping. In Aim 2 we will evaluate the independence of the SNPs associated with PSA discovered in the GWAS and the genes associated with PSA discovered in the TWAS using conditional analyses. We will then differentiate between genetic factors associated with PSA and those associated with PCa using conditional and mediation analyses. Based on these findings, we will create and test polygenic risk scores for PSA levels that combine associated genetic factors together into single, powerful measures. Finally, in Aim 3, we will use measured PSA levels and genetic factors—accounting for constitutive, non-PCa variability in PSA—to develop models that more accurately predict PCa outcomes. These models will allow us to assess the benefit of additionally incorporating genetic information with respect to deciding whether a man should undergo prostate biopsy. Our aims in aggregate are promising toward reducing screening harms while improving screening benefits. In translation, clinicians and patients could make more informed decisions, thereby reducing unnecessary procedures and diagnoses, and preventing poor outcomes.

抽象的 美国预防服务工作队（USPSTF）最近对前列腺特定的使用进行了评分 抗原（PSA）筛选前列腺癌（PCA）A“ C”：“对于55至69岁的男性，决定 进行定期基于PSA的前列腺癌筛查应该是个体，应包括 讨论临床筛查的潜在益处和危害。” USPSTF决定PSA 目前存在的筛选不足以实现宽度。因此，询问 疑问如何改善PSA筛查以减少过度诊断，过度治疗和PCA死亡率。 证据表明，将遗传因素纳入PSA筛查决策可以做到这一点。 PSA水平已被证明是高度遗传的，但是相关的遗传变异 到目前为止，仅解释了一些变化。而且，解释的变化甚至更小时 处理非欧洲人口。如果我们可以确定易于个人的遗传因素 高PSA级别独立于PCA，然后我们可以作为新PSA筛选的一部分来考虑它们 范例。我们建议通过一个大规模项目将17个研究的数据结合在一起 有和没有PCA，所有人都有对PSA水平和全基因组变异的数据。总而言之 研究包括653,076名男性，包括106,326名非洲血统，35,683名拉丁裔血统和 10,001个亚洲血统。在AIM 1中，我们将进行全面基因组协会研究（GWAS） PSA水平比以前的任何此类分析大20倍，也是有史以来第一个转录组 - PSA水平的广泛关联研究（TWA）。然后，我们将利用样本的多项式性质 通过精细映射发现与PSA相关的其他遗传变异。在AIM 2中，我们将评估 与GWA中发现的PSA相关的SNP的独立性和与PSA相关的基因 使用条件分析在TWA中发现。然后，我们将区分遗传因素 与PSA以及使用条件和中介分析相关的PSA以及与PCA相关联的相关。基于 这些发现，我们将为PSA水平创建和测试结合相关遗传的PSA水平的多基因风险评分 将因素共同成一个有力的测量。最后，在AIM 3中，我们将使用测量的PSA水平和遗传 因素 - 符合PSA的宪法性，非PCA的可变性，以开发更准确的模型 预测PCA结果。这些模型将使我们能够评估增加遗传的好处 有关决定一个人是否应该进行前列腺活检的信息。我们的总体目的是 有望减少筛查危害的同时改善筛查益处。在翻译，临床医生和 患者可以做出更明智的决定，从而减少不必要的程序和诊断，并 防止结果不佳。