The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia: A systematic review and meta-analysisResearch in context

Background: Methylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus (HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detecting high-grade cervical intra-epithelial neoplasia (CIN). Methods: We performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates. Findings: 44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamous intra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8–92·2))) vs. low-grade CIN (≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0–74·1))). Pooled difference in mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3% (95%CI:6·5–16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5–8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p