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

摘要 美国预防服务工作组（USPSTF）最近对前列腺特异性 A "C"："对于55至69岁的男性， 接受定期PSA为基础的前列腺癌筛查应该是一个人，并应包括 与他们的临床医生讨论筛查的潜在好处和危害。" USPSTF决定PSA 目前存在的筛选不足以广泛实施。因此，重要的是要问 如何改进PSA筛查以减少过度诊断、过度治疗和PCa死亡率的问题。 有证据表明，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，但相关的遗传变异，已被证明是非常重要的。 到目前为止，我们只发现了一些变化。此外，当 与非欧洲人打交道。如果我们能确定使个体倾向于 高PSA水平独立于PCa，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规模的项目来做这件事，该项目结合了17项男性研究的数据， 有和没有前列腺癌，所有人都有PSA水平和全基因组变异的数据。总之， 研究包括653，076名男性，其中包括106，326名非洲血统的男性，35，683名拉丁美洲血统的男性， 10,001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水平是以前任何此类分析的20倍，以及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， 通过精细定位发现与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PSA相关SNP与PSA相关基因的独立性 在TWAS中使用条件分析发现。然后我们将区分遗传因素 使用条件和中介分析与PSA相关和与PCa相关。基于 根据这些发现，我们将创建并测试PSA水平的多基因风险评分，该评分结合了联合收割机相关的遗传因素， 综合成一个单一的、强有力的衡量标准。最后，在目标3中，我们将使用测量的PSA水平和遗传学指标， 因素-解释PSA的组成性，非PCa变异性-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额外加入遗传物质的益处。 关于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 有望减少筛查的危害，同时提高筛查的益处。在翻译中，临床医生和 患者可以做出更明智的决定，从而减少不必要的程序和诊断， 防止不良后果。

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.