An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study

作者：Yifei Cheng, Lang Wu, Junyi Xin, Shuai Ben, Silu Chen, Huiqin Li, Lingyan Zhao, Meilin Wang, Gong Cheng, Mulong Du · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05190-y · 被引用次数：7 · 研究领域：Prostate Cancer Diagnosis and Treatment、Prostate Cancer Treatment and Research、Genetic Associations and Epidemiology

Abstract Background 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. Methods 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. Results 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; I 2 = 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 ( I 2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory...