期刊
EBIOMEDICINE
卷 50, 期 -, 页码 246-259出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2019.10.053
关键词
Human papillomavirus; DNA methylation; Cervical intraepithelial neoplasia; Cervical screening; Meta-analysis
资金
- National Institute of Health Research (NIHR) [NG0521]
- Imperial Health Charity [P73337]
- Genesis Research Trust [P73439]
- Wellcome Trust Imperial 4i/NIHR BRC [P77712]
- European Union [754936]
- Academy of Finland
- Helsinki-Uusimaa Hospital District
- Jalmari and Rauha Ahokas Foundation
- Sigrid Juselius Foundation
- DG Research and Innovation
- European Commission (Brussels, Belgium)
- European Society of Gynaecologic Oncology
- Haute Autoritede la Sante (Paris, France)
- Cancer Counsel NSW (Sydney, Australia)
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. <= CINULSIL 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. <= CINULSIL (p < 00001). 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. (C) 2019 The Authors. Published by Elsevier B.V.
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