Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Department of Environmental Genomics, School of Public Health, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
The Key Laboratory of Modern Toxicology of Ministry of Education, Department of Genetic Toxicology, School of Public Health, Center for Global Health, Nanjing Medical University, Nanjing, China.
J Transl Med. 2024 Apr 17;22(1):366. doi: 10.1186/s12967-024-05190-y.
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; I = 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 = 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.
早发性前列腺癌（EOPC，≤55 岁）具有独特的临床实体，具有较高的遗传风险，但大多数 EOPC 患者仍有很大机会早期发现，从而避免不利的预后。对基于年龄的前列腺癌（PCa）多基因风险评分（PRS）的精细理解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 167517 名男性参与者[4882 例病例，包括 205 例 EOPC 和 4677 例晚发性 PCa（LOPC）]。从年龄特异性全基因组关联研究中得出一般、EOPC 和 LOPC-PRS。使用加权 Cox 比例风险模型估计 PRS 与 PCa 相关的风险。使用来自 PLCO 和 TCGA 的另外 4238 名男性的时间依赖性接受者操作特征（ROC）曲线验证 PRS 的判别能力。进行基于孟德尔随机化的表型全基因组关联研究，以发现与 EOPC 相关的表型。
通过既定风险变异计算的 269-PRS 与 EOPC 风险的相关性更强[风险比（HR）=2.35，95%置信区间（CI）1.99-2.78]，而与 LOPC 的相关性较弱（HR=1.95，95%CI 1.89-2.01；I=79%）。EOPC-PRS 与 EOPC 风险显著相关（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 的风险估计相似（I=0%）。特别是，EOPC-PRS 对 EOPC 的判别能力最佳（ROC 下面积=0.613）。在 ProAP 平台上（前列腺癌基于年龄的表型全基因组关联研究；https://mulongdu.shinyapps.io/proap）中与 PCa 相关的表型因素中，EOPC 与 PCa 家族史相关，而 LOPC 与环境和生活方式暴露相关。
本研究全面描述了 EOPC 的独特遗传和表型结构。EOPC-PRS 可能会优化年轻男性的 PCa 风险估计，特别是那些没有家族史的男性，从而为精准人群分层提供指导。
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