Quantitative Measurement of L1 Human Papillomavirus Type 16 Methylation for the Prediction of Preinvasive and Invasive Cervical Disease

Kottaridi, Christine; Kyrgiou, Maria; Pouliakis, Abraham; Μαγκανά, Μαρία; Aga, Evangelia; Spathis, Aris; Mitra, Anita; Makris, George; Chrelias, Charalampos; Mpakou, Vassiliki; Paraskevaidis, Evangelos; Panayiotides, John; Karakitsos, Petros

doi:10.1093/infdis/jiw645

Cited by 18 publications

(18 citation statements)

References 39 publications

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“…Among the 43 included studies and 16,336 women, nine (20.9%) evaluated DNA methylation as part of population-based screening among women with screening test abnormality (from here on referred to as a referral-population-based studies; eight among HR-HPV-positive women 24,26–32 and one among HPV16-positive women with abnormal cytology 33 ), eight (18.6%) among women enrolled in cross-sectional or prospective cohort studies, 34–41 six (14.0%) using a case-control design, 10,25,42–44 eleven (26%) using convenience sampling 30,45–54 and nine (21%) among women with HPV16 infection (two cohort, 55,56 four case-control 57–60 and three convenience studies; 61–63 Table 1). There was one randomised controlled non-inferiority trial 64 not included in the review, which randomly allocated women who tested positive for HR-HPV to either triage by cytology or DNA methylation.…”

Section: Resultsmentioning

confidence: 99%

Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 99%

Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis

et al. 2019

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“…New biomolecular markers have the potential to allow the detection of CIN2 lesions with a true procarcinogeneic potential. Among many, HPV methylation and the microbiological markers have been shown in cross sectional studies to correlate to disease severity, and data on serial longitudinal samples are still awaited 7475767778…”

Section: Discussionmentioning

confidence: 99%

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis

Tainio

Athanasiou

Tikkinen

et al. 2018

BMJ

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257

242

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ObjectiveTo estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016.Eligibility criteriaStudies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months.Data synthesisTwo reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I2 statistics.Main outcome measuresRates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months).Results36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I2=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I2=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I2=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I2=0%), 23% (two studies, 226/938 women, 20% to 26%; I2=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I2=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%.ConclusionsMost CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.Systematic review registrationPROSPERO 2014: CRD42014014406.

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“…One of the epigenetic mechanisms that are increasingly studied is HPV genes' methylation. At present, a consistent correlation of increased methylation of capsid viral genes with histology severity is referred by the researchers 7, 9, 11, 19, 20. On the other hand, studies on methylation status of the UTR , E6 and E7 regions reveal heterogeneous and rather inconclusive results 21-25.…”

Section: Discussionmentioning

confidence: 65%

“…These included the sensitivity (Sens), specificity (Spec), positive (PPV) and negative predictive value (NPV), the false positive (FPR) and false negative (FNR) rate, the overall accuracy (OA) and the positive (PLR) and negative likelihood ratio (NLR). These parameters were calculated from methylation percentage 0% and increased up to 100% using an increment step of 0.1%, as described in our previous studies 7, 15-17. Subsequently graphs depicting sensitivity, specificity and overall accuracy for all methylation positions were produced and the above measures were reported for two positions, i.e.…”

Section: Methodsmentioning

confidence: 99%

“…The quantification of the percentage of cytosines with a covalently added methyl-group at individual CpG (Cytosine—phosphate—Guanine) dinucleotides reflects the degree of epigenetic changes of the viral genome. Many studies mainly focused on L1 viral gene, have already shown that the methylation percentage of HPV 16 specific CpG sites along this viral gene, is increasing gradually and it is highest in women with high-grade cervical neoplasia 7-10.…”

Section: Introductionmentioning

confidence: 99%

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Searching HPV genome for methylation sites involved in molecular progression to cervical precancer

Kottaridi¹,

Leventakou²,

Pouliakis³

et al. 2019

J. Cancer

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Background: Human Papilloma Virus has been considered as the main cause for cervical cancer. In this study we investigated epigenetic changes and especially methylation of specific sites of HPV genome. The main goal was to correlate methylation status with histological grade as well as to determine its accuracy in predicting the disease severity by establishing optimum methylation cutoffs.Methods: In total, sections from 145 cases genotyped as HPV16 were obtained from formalin- fixed, paraffin-embedded tissue of cervical biopsies, conization or hysterectomy specimens. Highly accurate pyrosequencing of bisulfite converted DNA, was used to quantify the methylation percentages of UTR promoter, enhancer and 5' UTR, E6 CpGs 494, 502, 506 and E7 CpGs 765, 780, 790. The samples were separated in different groupings based on the histological outcome. Statistical analysis was performed by SAS 9.4 for Windows and methylation cutoffs were identified by MATLAB programming language.Results: The most important methylation sites were at the enhancer and especially UTR 7535 and 7553 sites. Specifically for CIN3+ (i.e. HSIL or SCC) discrimination, a balanced sensitivity vs. specificity (68.1%, 66.2% respectively) with positive predictive value (PPV) and negative predictive value (NPV) (66.2%, 68.2% respectively) was achieved for UTR 7535 methylation of 6.1% cutoff with overall accuracy 67.1%, while for UTR 7553 a sensitivity 60.9%, specificity 69.0%, PPV=65.6%, NPV=64.5% and overall accuracy=65.0% at threshold 10.1% was observed.Conclusion: Viral HPV16 genome was found methylated in NF-1 binding sites of UTR in cases with high grade disease. Methylation percentages of E6 and E7 CpG sites were elevated at the cancer group.

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Quantitative Measurement of L1 Human Papillomavirus Type 16 Methylation for the Prediction of Preinvasive and Invasive Cervical Disease

Abstract: Elevated methylation level is associated with increased disease severity and has good ability to discriminate HPV16-positive women that have high-grade disease or worse.

Cited by 18 publications

References 39 publications

Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis

Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis

Searching HPV genome for methylation sites involved in molecular progression to cervical precancer

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