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HPV and DNA Methylation Testing in Urine for Cervical Intraepithelial Neoplasia and Cervical Cancer Detection.

  • van den Helder, Rianne1, 2
  • Steenbergen, Renske D M2
  • van Splunter, Annina P2
  • Mom, Constantijne H3
  • Tjiong, Ming Y3
  • Martin, Ivonne4
  • Rosier-van Dunné, Fleur M F5
  • van der Avoort, Irene A M6
  • Bleeker, Maaike C G2
  • van Trommel, Nienke E1
  • 1 Department of Gynecologic Oncology, Antoni van Leeuwenhoek/Netherlands Cancer Institute, Center of Gynecologic Oncology Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 2 Department of Pathology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 3 Department of Gynecologic Oncology, Amsterdam UMC, Amsterdam Medical Center, Center of Gynecologic Oncology Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 4 Department of Obstetrics and Gynecology, Tergooi MC, Blaricum, the Netherlands. , (Netherlands)
  • 5 Department of Obstetrics and Gynecology, Ikazia Ziekenhuis, Rotterdam, the Netherlands. , (Netherlands)
  • 6 Department of Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
Published Article
Clinical Cancer Research
American Association for Cancer Research
Publication Date
May 13, 2022
DOI: 10.1158/1078-0432.CCR-21-3710
PMID: 35266975


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. ©2022 American Association for Cancer Research.

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