DNA methylation of imprinted gene control regions in the regression of low-grade cervical lesions

Int J Cancer. 2018 Aug 1;143(3):552-560. doi: 10.1002/ijc.31350. Epub 2018 Mar 30.


The role of host epigenetic mechanisms in the natural history of low-grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression. A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow-up visits over 3 years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine-phosphate-guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non-regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time-point), adjusting for age, race, high-risk HPV (hrHPV), parity, oral contraceptive and smoking status. Median participant age was 26.6 years (range: 21.0-64.4 years), 39% were African-American, and 11% were current smokers. Most participants were hrHPV-positive at enrollment (80.5%). Over one-third of cases regressed (n = 53, 35.1%). Median time-to-regression was 12.6 months (range: 4.5-24.0 months). Probability of CIN1 regression was negatively correlated with methylation at IGF2AS CpG 5 (HR = 0.41; 95% CI = 0.23-0.77) and PEG10 DMR (HR = 0.80; 95% CI = 0.65-0.98). Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening.

Keywords: HPV; cervical cancer; epigenetics; imprinted genes; methylation; neoplasia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • CpG Islands
  • DNA Methylation*
  • Disease Progression
  • Epigenesis, Genetic
  • Female
  • Genomic Imprinting*
  • Humans
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Regulatory Sequences, Nucleic Acid*
  • Uterine Cervical Neoplasms / epidemiology
  • Uterine Cervical Neoplasms / etiology
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology*
  • Young Adult