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 Oštrbenk; Mario Poljak; Ate G J van der Zee; Ed Schuuring; G Bea A Wisman

doi:10.1002/ijc.31897

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

Int J Cancer. 2019 Feb 15;144(4):746-754. doi: 10.1002/ijc.31897. Epub 2018 Oct 31.

Authors

Robert W van Leeuwen¹, Anja Oštrbenk², Mario Poljak², Ate G J van der Zee¹, Ed Schuuring³, G Bea A Wisman¹

Affiliations

¹ Department of Gynaecologic Oncology, Cancer Research Centre Groningen, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
² Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
³ Department of Pathology, Cancer Research Centre Groningen, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

Abstract

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 × 10^-5 ) and C13orf18/EPB41L3/JAM3 (66%, 132/200, p = 2 × 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.

Keywords: (pre)malignant cervical cancer; DNA methylation markers; cervical cancer screening; high-risk human papillomavirus (hrHPV); triage test.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Biomarkers, Tumor / genetics
Cohort Studies
Colposcopy
DNA Methylation*
Female
Humans
Mass Screening / methods*
Middle Aged
Papillomaviridae / physiology
Papillomavirus Infections / diagnosis
Papillomavirus Infections / genetics*
Papillomavirus Infections / virology
Sensitivity and Specificity
Triage / methods*
Uterine Cervical Dysplasia / diagnosis
Uterine Cervical Dysplasia / genetics*
Uterine Cervical Neoplasms / diagnosis
Uterine Cervical Neoplasms / genetics*

Substances

Biomarkers, Tumor