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

Gynecol Oncol. 2019 Aug;154(2):368-373. doi: 10.1016/j.ygyno.2019.06.002. Epub 2019 Jun 8.


Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Cervical intraepithelial neoplasia; Cervical screening; Cytology; DNA methylation; Genotyping; Human papillomavirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cervical Intraepithelial Neoplasia / classification
  • Cervical Intraepithelial Neoplasia / epidemiology
  • Cervical Intraepithelial Neoplasia / genetics*
  • Cytokines / isolation & purification*
  • DNA Methylation
  • Female
  • Human papillomavirus 16
  • Human papillomavirus 18
  • Humans
  • Kaplan-Meier Estimate
  • MicroRNAs / isolation & purification
  • Papillomavirus Infections / genetics
  • Predictive Value of Tests
  • Risk Assessment
  • Uterine Cervical Neoplasms / classification
  • Uterine Cervical Neoplasms / epidemiology
  • Uterine Cervical Neoplasms / genetics*


  • Cytokines
  • MIRN124-2 microRNA, human
  • MicroRNAs
  • TAFA4 protein, human