van den Helder Rianne, Steenbergen Renske D M, van Splunter Annina P, Mom Constantijne H, Tjiong Ming Y, Martin Ivonne, Rosier-van Dunné Fleur M F, van der Avoort Irene A M, Bleeker Maaike C G, van Trommel Nienke E
Department of Gynecologic Oncology, Antoni van Leeuwenhoek/Netherlands Cancer Institute, Center of Gynecologic Oncology Amsterdam, Amsterdam, the Netherlands.
Department of Pathology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands.
Clin Cancer Res. 2022 May 13;28(10):2061-2068. doi: 10.1158/1078-0432.CCR-21-3710.
Biomarker detection in urine offers a potential solution to increase effectiveness of cervical cancer screening programs by attracting nonresponders. In this prospective study, the presence of high-risk human papillomavirus (hrHPV) DNA and the performance of DNA methylation analysis was determined for the detection of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN2/3) in urine, and compared with paired cervicovaginal self-samples and clinician-taken cervical scrapes.
A total of 587 samples were included from 113 women with cervical cancer, 92 women with CIN2/3, and 64 controls. Samples were tested for hrHPV DNA and five methylation markers. Univariate and multivariate logistic regression and leave-one-out cross-validation were used to determine the methylation marker performance for CIN3 and cervical cancer (CIN3+) detection in urine. Agreement between samples was determined using Cohen kappa statistics and the Spearman correlation coefficients.
HrHPV presence was high in all sample types, 79% to 92%. Methylation levels of all markers in urine significantly increased with increasing severity of disease. The optimal marker panel (ASCL1/LHX8) resulted in an AUC of 0.84 for CIN3+ detection in urine, corresponding to an 86% sensitivity at a 70% predefined specificity. At this threshold 96% (109/113) of cervical cancers, 68% (46/64) of CIN3, and 58% (14/24) of CIN2 were detected. Between paired samples, a strong agreement for HPV16/18 genotyping and a fair to strong correlation for methylation was found.
HrHPV DNA and DNA methylation testing in urine offers a promising solution to detect cervical cancer and CIN2/3 lesions, especially for women currently unreached by conventional screening methods.
通过吸引未响应者，尿液中的生物标志物检测为提高宫颈癌筛查项目的有效性提供了一种潜在的解决方案。在这项前瞻性研究中，测定了尿液中高危型人乳头瘤病毒（hrHPV）DNA的存在情况以及DNA甲基化分析在检测宫颈癌和高级别宫颈上皮内瘤变（CIN2/3）方面的性能，并与配对的宫颈阴道自我样本和临床医生采集的宫颈刮片进行比较。
共纳入了587份样本，来自113例宫颈癌女性、92例CIN2/3女性和64例对照。对样本进行hrHPV DNA和5种甲基化标志物检测。采用单因素和多因素逻辑回归以及留一法交叉验证来确定尿液中CIN3和宫颈癌（CIN3+）检测的甲基化标志物性能。使用科恩kappa统计量和斯皮尔曼相关系数来确定样本之间的一致性。
所有样本类型中hrHPV的存在率都很高，为79%至92%。尿液中所有标志物的甲基化水平随着疾病严重程度的增加而显著升高。最佳标志物组合（ASCL1/LHX8）在尿液中检测CIN3+的曲线下面积（AUC）为0.84，在预定义特异性为70%时对应86%的灵敏度。在此阈值下，检测到96%（109/113）的宫颈癌、68%（46/64）的CIN3和58%（14/24）的CIN2。在配对样本之间，发现HPV16/18基因分型有很强的一致性，甲基化有中等至强的相关性。
尿液中的hrHPV DNA和DNA甲基化检测为检测宫颈癌和CIN2/3病变提供了一种有前景的解决方案，特别是对于目前未被传统筛查方法覆盖的女性。
