Long-term CIN3+ risk of HPV positive women after triage with FAM19A4/miR124-2 methylation analysis

• Published in: Gynecologic oncology 2019-08, Vol.154 (2), p.368-373
• Main Authors: Dick, Stèfanie, Kremer, Wieke W., De Strooper, Lise M.A., Lissenberg-Witte, Birgit I., Steenbergen, Renske D.M., Meijer, Chris J.L.M., Berkhof, Johannes, Heideman, Daniëlle A.M.
• Format: Article
• Language: English
• Subjects: Cervical intraepithelial neoplasia; Cervical screening; Cytology; DNA methylation; Genotyping; Human papillomavirus
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2019.06.002

This study evaluates the long-term risk for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV positive women triaged with FAM19A4/miR124-2 methylation analysis. In a post hoc analysis, data on FAM19A4/miR124-2 methylation, cytology, and HPV16/18 genotyping of HPV positive women (n = 1025) from a large population-based screening cohort with 14-year follow-up were evaluated. Cumulative CIN3+ incidences over 3 screening rounds (5-year intervals) of 4 triage strategies were compared: FAM19A4/miR124-2 methylation analysis, cytology, HPV16/18 genotyping with FAM19A4/miR124-2 methylation, and HPV16/18 genotyping with cytology. Kaplan-Meier estimates of 14-year cumulative CIN3+ incidence of HPV positive women with a negative methylation and a negative cytology triage test were comparable (16.3% and 15.6%, respectively). The cumulative CIN3+ incidence of methylation positive and cytology positive women were 39.8% and 46.5%, respectively. HPV16/18 genotyping with methylation and HPV16/18 genotyping with cytology resulted in the lowest 14-year cumulative CIN3+ incidence among triage negative women (10.7% and 10.0%, respectively), but cumulative CIN3+ incidence among triage positive women was lower (33.4% and 35.7%, respectively) compared with triage by methylation alone and cytology alone. Among HPV positive women of 30 years and older, a negative FAM19A4/miR124-2 methylation triage test provides a similar long-term CIN3+ risk compared with a negative cytology triage test. Because of their high CIN3+ risk, women with a positive methylation triage test could be referred for colposcopy. Therefore, FAM19A4/miR124-2 methylation analysis is a promising alternative to cytology for triage of HPV positive women. •A negative FAM19A4/miR124-2 methylation result provides a similar safety in HPV positive women compared to cytology.•CIN3+ risk following a positive methylation test justifies immediate colposcopy referral.•Triage with methylation analysis enables full molecular screening which is also applicable on self-collected material.