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Abstract
Introduction/Background Methylation of viral DNA has been proposed as a novel biomarker for triage of HPV positive women at screening.This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine its diagnostic test accuracy in detecting high-grade cervical intra-epithelial neoplasia (CIN) in HPV positive women.
Methodology We performed searches in MEDLINE, EMBASE and CENTRAL from inception to September 2018. 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 modelwere applied to determine pooled effect estimates.
Results 43 studies with 8775 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for ≥CIN2/HSIL (72·7% (47·8–92·2)) vs ≤CIN1/LSIL(44·4% (16·0–74·1)). The pooled difference in mean methylation level was significantly higher in ≥CIN2/HSIL vs ≤CIN1/LSILfor the HPV16 L1 gene (11·3% (6·5–16·1)). The pooled odds ratio of HPV16 methylation in the L1 gene was 6·57 (3·49–12·39) for ≥CIN2/HSIL vs. ≤CIN1/LSIL. HPV16 L1/L2 genes performed best in predicting CIN2 or worse (pooled sensitivity 77% (63–87), specificity 64% (55–71), area under the curve (AUC) 0·73 (0·69–0·76)) (figure 1). HPV16 L1/L2 methylation improved triage of HPV16 positive women (figure 2).
Conclusion Higher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. The direct clinical use of this marker in triage is limited by the need of a multi-genotype assay. Next-generation multiplex sequencing assays containing all HPV types are under development and have the potential to allow rapid, automated and low-cost methylation testing.
Disclosure Funded by NIHR, Genesis Research Trust, Imperial Healthcare Charity, European Unions Horizon 2020, Wellcome Trust PhD Fellowship. No conflicts of interest.
Diagnostic accuracy of HPV16 L1/L2 in predicting CIN2/HSIL or worse1: Qiu (1) 2015; 2: Qiu (2) 2015; 3: Mirabello 2015; 4: Mirabello 2013; 5: Brentnall 2014; 6: Louvanto 2015; 7: Lorincz 2013; 8: Kottaridi 2017; 9: Marongiu 2014; 10: Lorincz 2016, 95%CI: 95% confidence intervals. df: degrees of freedom; 12: I2 statistic measure of heterogeneity; P: p-value; Q: Cochrane Q-test
Pre- and post methylation test probability of CIN2/3 in HPV16 positive womenPre: pre-test probability; Post: post-test probability