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

Sarah J Bowden; Ilkka Kalliala; Areti A Veroniki; Marc Arbyn; Anita Mitra; Kostas Lathouras; Lisa Mirabello; Marc Chadeau-Hyam; Evangelos Paraskevaidis; James M Flanagan; Maria Kyrgiou

doi:10.1016/j.ebiom.2019.10.053

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

EBioMedicine. 2019 Dec:50:246-259. doi: 10.1016/j.ebiom.2019.10.053. Epub 2019 Nov 12.

Authors

Affiliations

¹ Department of Surgery and Cancer, 3rd Floor IRDB, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN, London, UK; West London Gynaecology Cancer Centre, Hammersmith Hospital, Imperial Healthcare NHS Trust, UK.
² Department of Surgery and Cancer, 3rd Floor IRDB, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN, London, UK; Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Finland.
³ Department of Surgery and Cancer, 3rd Floor IRDB, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN, London, UK; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada; Department of Primary Education, School of Education, University of Ioannina, Ioannina, Greece.
⁴ Unit of Cancer Epidemiology, Scientific Institute of Public Health, Brussels, Belgium.
⁵ West London Gynaecology Cancer Centre, Hammersmith Hospital, Imperial Healthcare NHS Trust, UK.
⁶ Department of Clinical Genetics, National Institute of Health (NIH), Bethesda, MD, USA.
⁷ Department of Surgery and Cancer, 3rd Floor IRDB, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN, London, UK.
⁸ Department of Obstetrics and Gynaecology, University Hospital of Ioannina, Ioannina, Greece.
⁹ Department of Surgery and Cancer, 3rd Floor IRDB, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN, London, UK; West London Gynaecology Cancer Centre, Hammersmith Hospital, Imperial Healthcare NHS Trust, UK. Electronic address: m.kyrgiou@imperial.ac.uk.

Abstract

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 < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse (pooled sensitivity 77% (95%CI:63-87), specificity 64% (95%CI:55-71), area under the curve (0·73 (95%CI:0·69-0·77)).

Interpretation: 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. Direct clinical use is limited by the need for a multi-genotype and standardised assays. Next-generation multiplex HPV sequencing assays are under development and allow potential for rapid, automated and low-cost methylation testing.

Funding: NIHR, Genesis Research Trust, Imperial Healthcare Charity, Wellcome Trust NIHR Imperial BRC, European Union's Horizon 2020.

Keywords: Cervical intraepithelial neoplasia; Cervical screening; DNA methylation; Human papillomavirus; Meta-analysis.

Publication types

Meta-Analysis
Systematic Review

MeSH terms

CpG Islands
DNA Methylation*
DNA, Viral*
Female
Human papillomavirus 16 / genetics
Humans
Neoplasm Grading
Neoplasm Staging
Odds Ratio
Papillomaviridae / classification
Papillomaviridae / genetics*
Papillomavirus Infections / complications*
Papillomavirus Infections / virology*
ROC Curve
Uterine Cervical Dysplasia / diagnosis*
Uterine Cervical Dysplasia / etiology*

Substances

DNA, Viral

Grants and funding

WT_/Wellcome Trust/United Kingdom