PO.PS01.07 · 人群科学
将多基因风险评分与PSA检测相结合用于接受前列腺活检男性的前列腺癌风险分层
Incorporation of polygenic risk scores with PSA testing for prostate cancer risk stratification in men undergoing prostate biopsy
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摘要 Abstract
中文摘要
目的:虽然前列腺特异性抗原(PSA)筛查可降低前列腺癌(PC)死亡率,但其有限的区分能力导致惰性疾病的过度诊断和临床显著PC的漏诊。利用多基因评分的遗传学指导筛查策略可能改善PC的早期检测。我们假设,将PC风险的多基因评分(PHS601)和良性PSA升高的多基因评分(PRS447)与传统风险因素相结合,将改善在多样化人群中前列腺活检时对临床显著PC的预测。
方法:我们使用VA企业数据仓库,识别了1999年10月至2021年9月期间接受首次前列腺活检的退伍军人,遗传数据来自百万退伍军人计划。我们排除了既往有PC诊断的患者、活检前90天内无PSA的患者以及PSA水平>50 ng/mL的患者。该队列包括25,222名男性:19,376名(76.8%)白人,4,891名(19.4%)黑人或非裔美国人,以及955名(3.8%)其他种族/族裔。主要结局是临床显著PC(Gleason评分≥7)。我们评估了两个遗传评分(PHS601和PSA447,均标准化为z分数),连同活检前PSA、首次活检年龄、种族/族裔和吸烟状态。我们使用三个递进模型进行多变量逻辑回归:单独临床特征、临床特征加PHS601,以及临床特征加两个遗传评分。
结果:在25,222名患者中,8,319名(32.9%)被诊断为临床显著PC。两个遗传评分均显示出强独立关联:PHS601升高增加风险(OR=1.73,95%CI:1.68-1.79,P<0.001),而PSA447较高则降低风险(OR=0.69,95%CI:0.67-0.72,P<0.001)。在PSA为4 ng/mL时,临床显著癌症的预测概率在各PHS601百分位组(≤第2百分位至≥第98百分位)间从9.1%到56.9%不等。模型区分度从0.635(单独临床特征)提高到0.714(加PHS601)再到0.737(两个遗传评分,p<0.001)。
结论:与单独的传统风险因素相比,PC风险和良性PSA升高的多基因评分显著改善了活检时对临床显著PC的预测。这些发现支持遗传学指导的PC筛查策略。遗传PC风险低的男性可推迟活检至更高的PSA值,从而减少过度诊断,而遗传风险高的男性可在更低的PSA阈值时接受活检,从而减少临床显著PC的漏诊。
查看英文原文 English abstract
Purpose: While prostate-specific antigen (PSA) screening reduces prostate cancer (PC) mortality, limited discriminatory ability leads to overdiagnosis of indolent disease and missed clinically significant PC. Genetically informed screening strategies utilizing polygenic scores may improve early PC detection. We hypothesized that incorporating polygenic scores for PC risk (PHS601) and benign elevated PSA (PRS447) with traditional risk factors would improve prediction of clinically significant PC on prostate biopsy in a diverse population.
Methods: We identified veterans who underwent their first prostate biopsy from October 1999 to September 2021 using the VA Corporate Data Warehouse, with genetic data from the Million Veteran Program. We excluded patients with prior PC diagnosis, those without pre-biopsy PSA within 90 days, and PSA levels >50 ng/mL. The cohort included 25,222 men: 19,376 (76.8%) White, 4,891 (19.4%) Black or African American, and 955 (3.8%) other race/ethnicities. The primary outcome was clinically significant PC (Gleason score ≥7). We evaluated two genetic scores (PHS601 and PSA447, both standardized to z-scores) along with pre-biopsy PSA, age at first biopsy, race/ethnicity, and smoking status. We performed multivariable logistic regression using three progressive models: clinical features alone, clinical features plus PHS601, and clinical features plus both genetic scores.
Results: Among 25,222 patients, 8,319 (32.9%) were diagnosed with clinically significant PC. Both genetic scores showed strong independent associations: elevated PHS601 increased risk (OR=1.73, 95% CI: 1.68-1.79, P<0.001), while higher PSA447 decreased risk (OR=0.69, 95% CI: 0.67-0.72, P<0.001). At PSA of 4 ng/mL, predicted probabilities of clinically significant cancer ranged from 9.1% to 56.9% across PHS601 percentile groups (≤2nd to ≥98th). Model discrimination improved from 0.635 (clinical features alone) to 0.714 (plus PHS601) to 0.737 (both genetic scores, p<0.001).
Conclusion: Polygenic scores for PC risk and benign PSA elevation significantly improve prediction of clinically significant PC on biopsy compared to traditional risk factors alone. These findings support genetically informed PC screening strategies. Men with low genetic PC risk could defer biopsy until higher PSA values, reducing overdiagnosis, while those with high genetic risk could undergo biopsy at lower PSA thresholds, reducing missed clinically significant PC.
利益披露 Disclosure
D. Sabater Minarim, None..
R. Karunamuni, None..
K. M. Morgan, None..
T. Nelson, None..
C. Teerlink, None..
J. Lynch, None..
I. P. Garraway, None..
A. M. Dornisch, None..
T. M. Seibert, None..
J. L. Vassy, None..
B. S. Rose, None.