结合PRS特异性和年龄特异性变异的风险适应性前列腺癌PSA筛查的初步效果

Preliminary effects of risk-adapted PSA screening for prostate cancer after integrating PRS-specific and age-specific variation

Frontiers in Genetics

影响因子:2.8

分区:生物学3区 / 遗传学3区

发表日期:2024

作者: Xiaomin Liu, Hongyuan Duan, Siwen Liu, Yunmeng Zhang, Yuting Ji, Yacong Zhang, Zhuowei Feng, Jingjing Li, Ya Liu, Ying Gao, Xing Wang, Qing Zhang, Lei Yang, Hongji Dai, Zhangyan Lyu, Fangfang Song, Fengju Song, Yubei Huang

DOI: 10.3389/fgene.2024.1387588

摘要

尽管前列腺癌（PCa）的风险在不同年龄段和遗传风险中存在差异，但针对PCa的遗传特异性和年龄特异性前列腺特异性抗原（PSA）筛查的效果尚不明确。构建了加权和未加权的多基因风险评分（PRS），以将来自PLCO试验的参与者划分为低PRS组或高PRS组。利用时间依赖的受试者工作特征曲线和曲线下面积（tdAUC）确定用于PCa筛查的PSA的年龄特异性和PRS特异性临界值。将整合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筛查在准确性、高级别PCa（Gleason评分≥7）检测率和假阳性率方面进行了比较。以80个与PCa显著相关的SNPs构成的加权PRS被确定为最优PR，AUC为0.631。在PRS分层后，PSA检测10年PCa风险的tdAUC在低PRS和高PRS组分别为0.818和0.816，而对应的临界值分别为1.42和1.62 ng/mL。进一步按年龄分层，低PRS组的年龄特异性PSA临界值相对较低（<60岁、60-64岁、65-69岁和≥70岁的临界值分别为1.42、1.65、1.60和2.24 ng/mL），高PRS组的临界值则较高（1.48、1.47、1.89和2.72 ng/mL）。进一步分析显示，阳性PSA与高PRS在PCa发病率和死亡率上存在明显的交互作用。在不同年龄和PRS子组中，PSA阴性（-）的PCa风险差异非常小，而PSA阳性（+）与年龄和PRS呈显著相关，且高PRS/PSA（+）在≥70岁参与者中的风险最高[风险比（95%置信区间）：16.00（12.62-20.29）和19.48（9.26-40.96）]。推荐的筛查策略不仅降低了12.8%的漏诊PCa，还确保了较高的特异性，但不会导致比传统PSA筛查更多的假阳性。结合PRS特异性和年龄特异性临界值的风险适应性筛查比传统PSA筛查更为有效。

Abstract

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.