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 美国预防服务工作组 (USPSTF) 最近对前列腺特异性药物的使用进行了分级 抗原 (PSA) 筛查前列腺癌 (PCa) a “C”：“对于 55 至 69 岁的男性，决定 定期进行基于 PSA 的前列腺癌筛查应该是针对个体的筛查，并且应包括 与临床医生讨论筛查的潜在益处和危害。” USPSTF 决定 PSA 目前的筛查不足以广泛实施。因此，重要的是要询问 问题如何改进 PSA 筛查以减少过度诊断、过度治疗和 PCa 死亡率。 有证据表明，将遗传因素纳入 PSA 筛查决策中可以做到这一点。 PSA 水平已被证明具有高度遗传性，但相关的遗传变异已被证实 迄今为止确定的仅解释了一些变化。此外，当 与非欧洲人口打交道。如果我们能够确定导致个体易感的遗传因素 独立于 PCa 的高 PSA 水平，然后我们可以将其作为新 PSA 筛查的一部分 范例。我们建议通过一个大型项目来实现这一目标，该项目结合了 17 项针对男性和女性的研究数据。 无论有或没有 PCa，他们都拥有 PSA 水平和全基因组变异的数据。总而言之， 研究对象包括 653,076 名男性，其中 106,326 名非洲裔男性、35,683 名拉丁裔男性，以及 10,001 名亚洲血统。在目标 1 中，我们将进行多祖先全基因组关联研究 (GWAS) PSA 水平比之前任何此类分析高 20 倍，并且是有史以来第一个转录组 PSA 水平的广泛关联研究 (TWAS)。然后，我们将利用样本的多祖先性质 通过精细绘图发现与 PSA 相关的其他遗传变异。在目标 2 中，我们将评估 GWAS 中发现的与 PSA 相关的 SNP 以及与 PSA 相关的基因的独立性 使用条件分析在 TWAS 中发现。然后我们将区分遗传因素 使用条件和中介分析来分析与 PSA 相关的数据以及与 PCa 相关的数据。基于 根据这些发现，我们将创建并测试结合相关遗传的 PSA 水平的多基因风险评分 将各种因素整合为单一而有力的措施。最后，在目标 3 中，我们将使用测量的 PSA 水平和遗传 因素——考虑 PSA 的构成性、非 PCa 变异——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额外纳入遗传的好处 有关决定男性是否应该接受前列腺活检的信息。我们的总体目标是 有望减少筛查危害，同时提高筛查效益。在翻译中，临床医生和 患者可以做出更明智的决定，从而减少不必要的手术和诊断，以及 防止不良结果。