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

被引：45

作者：

Bowden, Sarah J. ^{[1
,2
]}

Kalliala, Ilkka ^{[1
,3
,4
]}

Veroniki, Areti A. ^{[1
,5
,6
]}

Arbyn, Marc ^{[7
]}

Mitra, Anita ^{[1
,2
]}

Lathouras, Kostas ^{[2
]}

Mirabello, Lisa ^{[8
]}

Chadeau-Hyam, Marc ^{[1
]}

Paraskevaidis, Evangelos ^{[9
]}

Flanagan, James M. ^{[1
]}

Kyrgiou, Maria ^{[1
,2
]}

机构：

[1] Imperial Coll London, Fac Med, IRDB, Dept Surg & Canc, 3rd Floor,Hammersmith Campus,Du Cane Rd, London W12 0NN, England

[2] Imperial Healthcare NHS Trust, Hammersmith Hosp, West London Gynaecol Canc Ctr, London, England

[3] Univ Helsinki, Dept Obstet & Gynaecol, Helsinki, Finland

[4] Helsinki Univ Hosp, Helsinki, Finland

[5] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON, Canada

[6] Univ Ioannina, Sch Educ, Dept Primary Educ, Ioannina, Greece

[7] Sci Inst Publ Hlth, Unit Canc Epidemiol, Brussels, Belgium

[8] NIH, Dept Clin Genet, Bldg 10, Bethesda, MD 20892 USA

[9] Univ Hosp Ioannina, Dept Obstet & Gynaecol, Ioannina, Greece

来源：

EBIOMEDICINE | 2019年 / 50卷

基金：

英国惠康基金; 芬兰科学院;

关键词：

Human papillomavirus; DNA methylation; Cervical intraepithelial neoplasia; Cervical screening; Meta-analysis; E2; BINDING-SITES; RESOLUTION MELTING ANALYSIS; HPV; 16; METHYLATION; L1; GENE; QUANTITATIVE MEASUREMENT; POTENTIAL BIOMARKER; CPG METHYLATION; MESSENGER-RNA; TYPE-16; DNA; E6;

D O I：

10.1016/j.ebiom.2019.10.053

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：246 / 259

页数：14

共 76 条

[1] High statistical heterogeneity is more frequent in meta-analysis of continuous than binary outcomes [J].