Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes. The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99–2.78] than LOPC (HR = 1.95, 95% CI 1.89–2.01; I2 = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98–5.54) but not to LOPC (HR = 0.98, 95% CI 0.96–1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancer Age-based PheWAS; https://mulongdu.shinyapps.io/proap ), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures. This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.

中文翻译：

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早发特定多基因风险评分优化前列腺癌基于年龄的风险评估和分层：基于人群的队列研究

早发性前列腺癌（EOPC，≤55岁）具有独特的临床特征，具有较高的遗传风险，但大多数EOPC患者仍有很大机会被早期发现，因此预后不良。深入了解前列腺癌 (PCa) 基于年龄的多基因风险评分 (PRS) 对于个性化风险分层至关重要。我们纳入了来自英国生物银行的 167,517 名男性参与者 [4882 例，包括 205 例 EOPC 和 4677 例迟发性 PCa (LOPC)]。 General-、EOPC- 和 LOPC-PRS 源自年龄特异性全基因组关联研究。应用加权 Cox 比例风险模型来估计与 PRS 相关的 PCa 风险。 PRS 的辨别能力通过来自 PLCO 和 TCGA 的另外 4238 名男性的时间依赖性受试者工作特征 (ROC) 曲线进行了验证。孟德尔随机化基础上的全表型关联研究旨在发现 EOPC 关联表型。通过完善的风险变量计算得出的 269-PRS 与 EOPC 风险的相关性比 LOPC（HR = 1.95，95% CI 1.89）更密切[风险比 (HR) = 2.35，95% 置信区间 (CI) 1.99–2.78] –2.01；I2 = 79%）。 EOPC-PRS 与 EOPC 风险显着相关（HR = 4.70，95% CI 3.98–5.54），但与 LOPC 无关（HR = 0.98，95% CI 0.96–1.01），而 LOPC-PRS 对 EOPC 和 LOPC 具有相似的风险估计（I2 = 0%）。特别是，EOPC-PRS 对 EOPC 表现出了最佳的判别能力（ROC 下的面积 = 0.613）。在 ProAP（前列腺癌基于年龄的 PheWAS；https://mulongdu.shinyapps.io/proap）平台中存储的 PCa 表组因子中，EOPC 优先与 PCa 家族史相关，而 LOPC 易于与环境和生活方式暴露相关。这项研究全面描述了 EOPC 独特的遗传和表型结构。 EOPC-PRS 可以优化年轻男性（尤其是没有家族史的男性）PCa 的风险评估，从而为精确的人群分层提供指导。