Cervical cancer risk in HPV-positive women after a negative FAM19A4/mir124-2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow-up

Int J Cancer. 2018 Sep 15;143(6):1541-1548. doi: 10.1002/ijc.31539. Epub 2018 Apr 27.

Abstract

DNA methylation analysis of cervical scrapes using FAM19A4 and mir124-2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV-positive women. To date, longitudinal data on the cancer risk of methylation test-negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124-2 methylation analysis in an HPV-positive screening cohort with 14 years of follow-up. Archived HPV-positive cervical scrapes of 1,040 women (age 29-61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124-2 methylation. By linkage with the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow-up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124-2 methylation, including 24 women with cervical cancer in follow-up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow-up. Within screening round capability of FAM19A4/mir124-2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5-100). Kaplan-Meier estimate of 14-year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66-3.0) among baseline methylation-negative and 2.4% (95% CI: 1.4-3.6) among baseline cytology-negative women (risk difference: 0.71% [95% CI: 0.16-1.4]). In conclusion, a negative FAM19A4/mir124-2 methylation test provides a low cervical cancer risk in HPV-positive women of 30 years and older. FAM19A4/mir124-2 methylation testing merits consideration as an objective triage test in HPV-based cervical screening programs.

Keywords: DNA methylation; HPV testing; cancer risk; cervical screening; cytology; triage.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / etiology
  • Adenocarcinoma / genetics
  • Adult
  • Biomarkers, Tumor / genetics
  • Carcinoma, Squamous Cell / diagnosis
  • Carcinoma, Squamous Cell / etiology
  • Carcinoma, Squamous Cell / genetics
  • Case-Control Studies
  • Cervical Intraepithelial Neoplasia / diagnosis
  • Cervical Intraepithelial Neoplasia / etiology
  • Cervical Intraepithelial Neoplasia / genetics
  • Cohort Studies
  • Cytokines / genetics*
  • DNA Methylation*
  • Early Detection of Cancer*
  • Female
  • Follow-Up Studies
  • Genotype
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / isolation & purification
  • Human papillomavirus 18 / genetics
  • Human papillomavirus 18 / isolation & purification
  • Humans
  • MicroRNAs / genetics
  • Middle Aged
  • Netherlands
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / virology
  • Prognosis
  • Risk Factors
  • Survival Rate
  • Time Factors
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / etiology
  • Uterine Cervical Neoplasms / genetics
  • Vaginal Smears

Substances

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

Associated data

  • ISRCTN/ISRCTN20781131