Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
Nat Med. 2023 Jun;29(6):1412-1423. doi: 10.1038/s41591-023-02277-9. Epub 2023 Jun 1.
Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.
前列腺特异性抗原（PSA）筛查在前列腺癌中的应用仍存在争议，因为它会增加对临床意义不大的肿瘤的过度诊断和过度治疗。考虑到构成性、与癌症无关的 PSA 变化的遗传决定因素，有可能提高筛查的实用性。在这项研究中，我们在一项多血统荟萃分析中发现了 95768 名男性中 128 个全基因组显著关联（P < 5×10），并开发了一种 PSA 多基因评分（PGS），可解释 9.61%的构成性 PSA 变化。我们发现，在欧洲血统的男性中，使用 PGS 调整后的 PSA 可以避免高达 31%的阴性前列腺活检，但也会导致前列腺癌患者的活检减少 12%，这些患者主要是 Gleason 评分<7 的肿瘤。与未调整的 PSA 相比，遗传调整后的 PSA 更能预测侵袭性前列腺癌（优势比（OR）=3.44，P=6.2×10，曲线下面积（AUC）=0.755），而未调整的 PSA 则为（OR=3.31，P=1.1×10，AUC=0.738），在 106 例病例和 23667 例对照中。与单独的前列腺癌 PGS 相比（AUC=0.712），包括遗传调整后的 PSA 在内，可以提高侵袭性疾病的检测（AUC=0.786，P=7.2×10）。我们的研究结果强调了将 PGS 纳入前列腺癌筛查的个性化生物标志物的潜在实用性。
