Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy

Introduction
Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels.
Materials and Methods
Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men.
Results
The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)).
Conclusion
We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies.

引言
前列腺特异性抗原（Prostate-specific antigen, PSA）检测是目前临床广泛认可的前列腺癌筛查手段，但在保证良好灵敏度的阈值下，其特异性较低。既往研究已明确四种主要与循环PSA水平相关、而非前列腺癌发病风险相关的单核苷酸多态性（single nucleotide polymorphisms, SNPs）：TERT rs2736098、FGFR2 rs10788160、TBX3 rs11067228及KLK3 rs17632542。消除PSA水平的遗传影响因素，或可提升剩余由生物学因素决定的PSA变异度，从而更好地区分确诊前列腺癌患者的疾病进展高低风险。本研究旨在探讨纳入PSA相关SNPs的信息，是否能提升仅依靠单一PSA阈值对PSA水平升高人群的疾病进展风险区分能力。

材料与方法
纳入PSA水平处于3~10ng/mL且经组织病理学确诊为前列腺癌的男性患者，按疾病进展风险分为高低两组（低风险组：格里森评分≤6分且临床分期为T1-T2a期；高风险组：格里森评分7~10分或临床分期为T2C期）。本研究利用四种PSA相关SNPs的联合遗传效应，计算经遗传学校正的PSA风险评分。通过计算曲线下面积（Area under the Curve, AUC），评估经遗传学校正的PSA风险评分对高低进展风险患者的区分效能。

结果
本分析共纳入868例前列腺癌患者，其中低风险组684例（占比78.8%），高风险组184例（占比21.2%）。受试者工作特征（Receiver operating characteristic, ROC）曲线分析结果显示，纳入四种PSA相关SNPs并未提升检测PSA在区分前列腺癌高低风险患者中的筛查效能：单纯检测PSA的AUC为59.5%（95%置信区间：54.7~64.2），联合四种PSA相关SNPs信息后的AUC为59.8%（95%置信区间：55.2~64.5），组间比较P值为0.40。

结论
本研究证实，针对四种PSA相关SNPs的联合遗传效应对PSA进行遗传学校正，并未提升PSA水平升高（3~10ng/mL）人群的前列腺癌高低进展风险区分能力。后续可通过开展更大样本量的前瞻性研究并进行全基因组关联分析（Genome-Wide Association Study, GWAS），对四种PSA相关SNPs的效应进行验证与更精准的估计，同时筛选更多与PSA水平相关而非前列腺癌发病风险的遗传变异。