Khemees Tariq A, Yang Bing, Schultz Adam, Allen Glenn O, Gawdzik Joseph, Nihal Aman, Richards Kyle A, Abel E Jason, Jarrard David F
Department of Urology, School of Medicine and Public Health, University of Wisconsin-Madison Madison 53705, WI, USA.
Carbone Comprehensive Cancer Center, University of Wisconsin-Madison Madison 53705, WI, USA.
Am J Clin Exp Urol. 2021 Dec 15;9(6):479-488. eCollection 2021.
Prostate cancer (PC) development involves epigenetic DNA methylation changes that occur in the tumor. However, distinct DNA methylation changes have been previously found to encompass a widespread cancer field defect involving normal prostate tissue. In the current study, we analyzed a series of DNA methylation field markers to determine if they predict the presence of PC in urine. Urine samples were collected from patients undergoing prostate biopsy with biopsy-proven PC (90), and without PC (77). From the urine pellet, methylated DNA was quantified across several previously identified CpG island regions near the genes using bisulfite pyrosequencing. Univariate and multivariate analyses were performed. Urine cell pellets show significant increases in methylation in four of the markers from patients with PC compared to those without PC including 12.2 vs. 7.7%, 15.7 vs. 10.36%, 12.0 vs. 7.1%, and 12.2 vs. 8.3% [all P<0.01]. Area under the ROC Curve (AUCs) were generated for (0.74, Odds ratios (OR) 1.09; 95% confidence intervals (CI) 0.94-1.25, (0.72, OR 1.18; 95% CI 1.09-1.28) and (0.76, OR 1.35; 95% CI 1.199-1.51). In combination, a two-marker assay performs better than prostate specific antigen (PSA), AUC 0.77 vs. PSA AUC of 0.6 (P = 0.01) with the lowest error. In addition, distinguished between grade group 1 (GG1) and higher grade cancers (P<0.03). In conclusion, applying methylation of field defect loci to urine samples provides a novel approach to distinguish patients with and without cancer.
前列腺癌（PC）的发生涉及肿瘤中表观遗传DNA甲基化的变化。然而，先前已发现不同的DNA甲基化变化包含涉及正常前列腺组织的广泛癌症场缺陷。在本研究中，我们分析了一系列DNA甲基化场标记物，以确定它们是否能预测尿液中PC的存在。从接受前列腺活检且活检证实患有PC的患者（90例）和未患PC的患者（77例）中收集尿液样本。从尿沉渣中，使用亚硫酸氢盐焦磷酸测序对几个先前确定的靠近基因的CpG岛区域的甲基化DNA进行定量。进行了单变量和多变量分析。与未患PC的患者相比，患PC的患者的尿细胞沉渣在四种标记物中的甲基化显著增加，包括[具体标记物1]为12.2%对7.7%，[具体标记物2]为15.7%对10.36%，[具体标记物3]为12.0%对7.1%，以及[具体标记物4]为12.2%对8.3%[所有P<0.01]。生成了[具体标记物1]的ROC曲线下面积（AUC）为0.74，优势比（OR）为1.09；95%置信区间（CI）为0.94 - 1.25，[具体标记物2]的AUC为0.72，OR为1.18；95%CI为1.09 - 1.28，以及[具体标记物3]的AUC为0.76，OR为1.35；95%CI为1.199 - 1.51。联合使用两种标记物的检测方法比前列腺特异性抗原（PSA）表现更好，AUC为0.77，而PSA的AUC为0.6（P = 0.01），误差最低。此外，[具体标记物]能够区分1级（GG1）和更高等级的癌症（P<0.03）。总之，将场缺陷位点的甲基化应用于尿液样本提供了一种区分患癌和未患癌患者的新方法。
