DNA methylation markers as a triage test for identification of cervical lesions in a high risk human papillomavirus positive screening cohort

Robert W. van Leeuwen, Anja Ostrbenk, Mario Poljak, Ate G. J. van der Zee, Ed Schuuring, G. Bea A. Wisman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Objective triage strategies are required to prevent unnecessary referrals for colposcopy in population-based screening programs using primary high-risk human papillomavirus (hrHPV) testing. We have identified several DNA methylation markers with high sensitivity and specificity for detection of high-grade cervical intraepithelial neoplasia or worse (CIN2+) in women referred for colposcopy. Our study assessed diagnostic potential of these methylation markers in a hrHPV-positive screening cohort. All six markers (JAM3, EPB41L3, C13orf18, ANKRD18CP, ZSCAN1 and SOX1) showed similar association across histology in the hrHPV-positive cohort when compared to the Dutch cohort (each p > 0.15). Sensitivity for CIN2+ was higher using methylation panel C13orf18/EPB41L3/JAM3 compared to the other 2 panels (80% vs. 60% (ANKRD18CP/C13orf18/JAM3) and 63% (SOX1/ZSCAN1), p = 0.01). For CIN3+ all three methylation panels showed comparable sensitivity ranging from 68% (13/19) to 95% (18/19). Specificity of SOX1/ZSCAN1 panel (84%, 167/200) was considerably higher compared to ANKRD18CP/C13orf18/JAM3 (68%, 136/200, p = 2 x 10(-5)) and C13orf18/EPB41L3/JAM3 (66%, 132/200, p = 2 x 10(-7)). High negative predictive value (NPV) (91-95% and 96-99%) was observed for CIN2+ and CIN3+, for all three methylation panels, while positive predictive value (PPV) varied from 25 to 40% for CIN2+ and 15-27% for CIN3+. Interestingly, 118/235 samples were negative for all six markers (including 106 controls (89.8%), 6 CIN1 (5.1%), 5 CIN2 (4.2%) and 1 CIN3 (0.8%)). Methylation results from both independent cohorts were comparable as well as high sensitivity for detection of cervical cancer and its high-grade precursors in hrHPV-positive population. Our study therefore validates these methylation marker panels as triage test either in hrHPV-based or abnormal cytology-based screening programs.

Original languageEnglish
Pages (from-to)746-754
Number of pages9
JournalInternational Journal of Cancer
Issue number4
Publication statusPublished - 15-Feb-2019


  • (pre)malignant cervical cancer
  • DNA methylation markers
  • high-risk human papillomavirus (hrHPV)
  • cervical cancer screening
  • triage test
  • HPV
  • CADM1

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