Brikun Igor, Nusskern Deborah, Freije Diha
Euclid Diagnostics LLC, 9800 Connecticut Dr., Crown Point, IN 46307 USA.
Present Address: Luminex Corporation, 4088 Commercial Ave, Northbrook, IL 60062 USA.
Exp Hematol Oncol. 2019 Jun 27;8:13. doi: 10.1186/s40164-019-0137-x. eCollection 2019.
Prostate cancer diagnosis using the PSA test remains controversial because of overdiagnosis and overtreatment of potentially indolent cancers. There remains a need to increase the diagnostic lead time and to target treatment to patients with significant disease. One possible approach to overcome the limitations of PSA is to screen men for the molecular signature of early PCA, monitor the rate of disease progression and target treatment to patients who are likely to benefit from it. Such an approach requires a large panel of markers that define a molecular clock for PCA. We recently developed a panel of 19 markers for the non-invasive detection of PCA from urine DNA. It raised the possibility that additional methylation markers could be successfully analyzed from urine DNA, a prerequisite for increasing the diagnostic lead time and enabling disease monitoring.
We developed semi-quantitative polymerase chain reaction assays for 13 additional markers and determined their methylation status in 150 urine DNAs from 94 patients with elevated PSA. Eighty five samples were obtained following DRE and 65 samples were from first void. We combined the data of the 13 new markers with the previously reported 19 markers and calculated the sensitivity, specificity, negative and positive predictive values at every threshold from one to 32 positive markers.
Using 10of32 positive markers as the threshold to recommend a biopsy yields a sensitivity of 81% (95% CI 0.68-0.93) and 93% (95% CI 0.84-1.02) and a specificity of 76% (95% CI 0.63-0.88) and 77% (95% CI 0.63-0.91) from DRE and FV DNA, respectively. The PPV was 71% and 77% and the NPV was 85% and 93% from DRE and FV, respectively.
This study shows that large marker panels can be analyzed from urine DNA without loss of sensitivity or specificity. Using 32 markers improved the stratification of patients undergoing screening for PCA particularly for patients below the 10of32 threshold. The results show the utility of larger biomarker panels for PCA diagnosis and suggest that the development of the panels needed to monitor disease progression could be successfully accomplished.
由于对潜在惰性癌症的过度诊断和过度治疗，使用前列腺特异性抗原（PSA）检测进行前列腺癌诊断仍存在争议。仍需要延长诊断提前期，并将治疗靶向患有严重疾病的患者。克服PSA局限性的一种可能方法是对男性进行早期前列腺癌（PCA）分子特征筛查，监测疾病进展速度，并将治疗靶向可能从中受益的患者。这种方法需要一大组定义PCA分子时钟的标志物。我们最近开发了一组19种标志物，用于从尿液DNA中无创检测PCA。这增加了从尿液DNA中成功分析更多甲基化标志物的可能性，这是延长诊断提前期和实现疾病监测的先决条件。
我们为另外13种标志物开发了半定量聚合酶链反应检测方法，并确定了94例PSA升高患者的150份尿液DNA中的甲基化状态。85份样本在直肠指检（DRE）后获得，65份样本来自首次排尿。我们将13种新标志物的数据与先前报道的19种标志物的数据相结合，并计算了从1到32个阳性标志物的每个阈值下的敏感性、特异性、阴性和阳性预测值。
以32个阳性标志物中的10个作为推荐活检的阈值，DRE和首次排尿（FV）DNA的敏感性分别为81%（95%可信区间0.68 - 0.93）和93%（95%可信区间0.84 - 1.02），特异性分别为76%（95%可信区间0.63 - 0.88）和77%（95%可信区间0.63 - 0.91）。DRE和FV的阳性预测值分别为71%和77%，阴性预测值分别为85%和93%。
本研究表明，可以从尿液DNA中分析大型标志物组，而不会损失敏感性或特异性。使用32种标志物改善了接受PCA筛查患者的分层，特别是对于低于32个标志物中10个阈值的患者。结果显示了更大生物标志物组对PCA诊断的实用性，并表明监测疾病进展所需标志物组的开发可以成功完成。
