尽管不同年龄和遗传风险的前列腺癌 (PCa) 风险有所不同，但遗传特异性和年龄特异性前列腺特异性抗原 (PSA) 筛查对 PCa 的影响尚不清楚。加权和未加权多基因风险评分 (PRS)旨在将 PLCO 试验的参与者分为低 PRS 组或高 PRS 组。用于 PCa 筛查的 PSA 年龄特异性和 PRS 特异性截止值是通过时间依赖性受试者工作特征曲线和曲线下面积 (tdAUC) 确定的。将结合 PRS 特异性和年龄特异性 PSA 临界值的改进筛查策略与传统 PSA 筛查的准确性、高级别 PCa 检出率（格里森评分≥7）和假阳性率进行比较。具有 80 个 SNP 的加权 PRS与 PCa 显着相关被确定为最佳 PRS，AUC 为 0.631。按 PRS 分层后，低 PRS 组和高 PRS 组具有 10 年 PCa 风险的 PSA tdAUC 分别为 0.818 和 0.816，而截止值分别为 1.42 和 1.62 ng/mL。按年龄进一步分层后，低 PRS 的 PSA 年龄特异性临界值相对较低（<60、60-64、65-69 和 ≥70 岁的年龄为 1.42、1.65、1.60 和 2.24 ng/mL）年）高于高 PRS（1.48、1.47、1.89 和 2.72 ng/mL）。进一步分析显示，PSA 阳性和 PRS 高对 PCa 发病率和死亡率有明显的相互作用。在不同年龄和 PRS 的 PSA (-) 亚组中观察到 PCa 风险差异非常小，并且 PSA ( ) 的 PCa 发病率和死亡率随着年龄和 PRS 的增加而显着增加，参与者中高 PRS/PSA ( ) 的风险最高年龄 ≥70 岁 [HR (95% CI)：16.00 (12.62-20.29) 和 19.48 (9.26-40.96)]。推荐的筛查策略减少了 12.8% 的漏检 PCa，确保了高特异性，但不会导致比传统 PSA 筛查过多的假阳性。结合 PRS 特异性和年龄特异性 PSA 临界值的风险适应筛查比传统方法更有效PSA 筛查。版权所有 © 2024 刘、段、刘、张、季、张、冯、李、刘、高、王、张、杨、戴、吕、宋、宋和黄。

Although the risk of prostate cancer (PCa) varies across different ages and genetic risks, it's unclear about the effects of genetic-specific and age-specific prostate-specific antigen (PSA) screening for PCa.Weighed and unweighted polygenic risk scores (PRS) were constructed to classify the participants from the PLCO trial into low- or high-PRS groups. The age-specific and PRS-specific cut-off values of PSA for PCa screening were determined with time-dependent receiver-operating-characteristic curves and area-under-curves (tdAUCs). Improved screening strategies integrating PRS-specific and age-specific cut-off values of PSA were compared to traditional PSA screening on accuracy, detection rates of high-grade PCa (Gleason score ≥7), and false positive rate.Weighted PRS with 80 SNPs significantly associated with PCa was determined as the optimal PRS, with an AUC of 0.631. After stratifying by PRS, the tdAUCs of PSA with a 10-year risk of PCa were 0.818 and 0.816 for low- and high-PRS groups, whereas the cut-off values were 1.42 and 1.62 ng/mL, respectively. After further stratifying by age, the age-specific cut-off values of PSA were relatively lower for low PRS (1.42, 1.65, 1.60, and 2.24 ng/mL for aged <60, 60-64, 65-69, and ≥70 years) than high PRS (1.48, 1.47, 1.89, and 2.72 ng/mL). Further analyses showed an obvious interaction of positive PSA and high PRS on PCa incidence and mortality. Very small difference in PCa risk were observed among subgroups with PSA (-) across different age and PRS, and PCa incidence and mortality with PSA (+) significantly increased as age and PRS, with highest risk for high-PRS/PSA (+) in participants aged ≥70 years [HRs (95%CI): 16.00 (12.62-20.29) and 19.48 (9.26-40.96)]. The recommended screening strategy reduced 12.8% of missed PCa, ensured high specificity, but not caused excessive false positives than traditional PSA screening.Risk-adapted screening integrating PRS-specific and age-specific cut-off values of PSA would be more effective than traditional PSA screening.Copyright © 2024 Liu, Duan, Liu, Zhang, Ji, Zhang, Feng, Li, Liu, Gao, Wang, Zhang, Yang, Dai, Lyu, Song, Song and Huang.