Abstract
BackgroundTo conduct a meta-analysis of performance of DNA methylation in women with high-grade cervical intraepithelial neoplasia (CIN2+).MethodsMedline and Embase databases were searched for studies of methylation markers versus histological endpoints. Pooled sensitivity, specificity and positive predictive value (PPV) for CIN2+ were derived from bivariate models. Relative sensitivity and specificity for CIN2+ compared to cytology and HPV16/18 genotyping were pooled using random-effects models.ResultsSixteen thousand three hundred thirty-six women in 43 studies provided data on human genes (CADM1, MAL, MIR-124-2, FAM19A4, POU4F3, EPB41L3, PAX1, SOX1) and HPV16 (L1/L2). Most (81%) studies evaluated methylation assays following a high-risk (HR)-HPV-positive or abnormal cytology result. Pooled CIN2+ and CIN3+ prevalence was 36.7% and 21.5%. For a set specificity of 70%, methylation sensitivity for CIN2+ and CIN3+ were 68.6% (95% CI: 62.9–73.8) and 71.1% (95% CI: 65.7–76.0) and PPV were 53.4% (95% CI: 44.4–62.1) and 35.0% (95% CI: 28.9–41.6). Among HR-HPV+ women, the relative sensitivity of methylation for CIN2+ was 0.81 (95% CI: 0.63–1.04) and 1.22 (95% CI: 1.05–1.42) compared to cytology of atypical squamous cells of undetermined significance, or greater (ASCUS+) and HPV16/18 genotyping, respectively, while relative specificity was 1.25 (95% CI: 0.99–1.59) and 1.03 (95% CI: 0.94–1.13), respectively.ConclusionDNA methylation is significantly higher in CIN2+ and CIN3+ compared to ≤CIN1. As triage test, DNA methylation has higher specificity than cytology ASCUS+ and higher sensitivity than HPV16/18 genotyping.
Highlights
To conduct a meta-analysis of performance of DNA methylation in women with high-grade cervical intraepithelial neoplasia (CIN2+)
Study outcomes Studies were included if they reported the percentage of DNA methylation according to CIN grade, or sensitivity and specificity of the DNA methylation assays for the detection of the outcome, or if the receiver operating characteristic (ROC) curve was provided from which sensitivity and specificity estimates could be obtained
Inclusion and exclusion criteria Studies reporting methylation within biopsy specimens were excluded as we aimed to evaluate the performance of DNA methylation assays as a potential primary screening or triage tests when cervical swabs would be used
Summary
To conduct a meta-analysis of performance of DNA methylation in women with high-grade cervical intraepithelial neoplasia (CIN2+). Most (81%) studies evaluated methylation assays following a high-risk (HR)-HPV-positive or abnormal cytology result. In May 2018, the Director-General of the World Health Organization (WHO) made a global call for action towards the elimination of ICC calling for more innovative technologies for detection of precancerous lesions and better strategies to increase ICC screening coverage and uptake.[2] There is strong evidence that high-risk human papillomavirus (HR-HPV) DNA based screening is more sensitive for the detection of highgrade CIN (CIN2+) and is effective in prevention of ICC compared to cervical cytology and visual inspection.[3] HPV testing detects many transient infections, meaning that its specificity for high-grade CIN is low,[4] which has important implications for screening women with high prevalence of HRHPV. DNA methylation of human genes and HPV virus occur during HR-HPV infection and precancerous tissue progression, leading to alterations in the functions of gene products regulating tumour suppression.[6,7] Such aberrant
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