Methylation of viral and host genes and severity of cervical lesions associated with human papillomavirus type 16

Louvanto, Karolina; Franco, Eduardo L.; Ramanakumar, Agnihotram V.; Vasiljević, Nataša; Scibior‐Bentkowska, Dorota; Koushik, Anita; Cuzick, Jack; Coutlée, François; Lörincz, Attila T.

doi:10.1002/ijc.29196

Cited by 55 publications

(69 citation statements)

References 33 publications

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“…DNA methylation is a mitotically transmitted epigenetic motif that can be measured with good accuracy in tissue biopsies, exfoliated cells, blood and other fluids and can be related to exact physical locations in the genome; this feature lends itself more readily to medical diagnostics. Clinically relevant methylation changes are known in many human cancers such as cervix, prostate, breast, colon, bladder, stomach, oesophagus and lung cancers [1,[10][11][12] . Differential methylation may have a central role in the development and outcome of most if not all human malignancies.…”

Section: The Interface Of Epigenetics and Geneticsmentioning

confidence: 99%

“…A new and promising triage for hrHPV+ women is DNA methylation testing [1,8,10,17,27,28,30] . Methylation measurement can be done as a simple reflex to the original screening specimen.…”

Section: New Molecular Triage Tests For Hpv-positive Womenmentioning

confidence: 99%

“…The combination assay may have a greater sensitivity for CIN3 and a better unbiased area (AUC) under the receiver operator characteristic curve [35] . Almost all of the cancers can be detected in exfoliated cell samples by any of the 3 approaches, but catching cancers is not as important as catching pre-cancers [10,36] . The argument that an absence of detectable methylation in CIN2 and CIN3 identifies high-grade lesions that do not progress does postulate an interesting idea and if true would quickly revolutionize patient management strategies.…”

Section: Dna Methylation Testing: Viral or Host Targets?mentioning

confidence: 99%

“…Considering a combination reflex testing approach with hrHPV screening at a sensitivity and specificity of 95 and 90%, respectively, and applying a reflex methylation triage with an AUC of 0.9 to the hrHPV positives, we could expect a final molecular screening algorithm sensitivity and specificity of approximately 85 and 98%, respectively, for CIN2/3 in the first round of screening. Close to 100% of the cervical cancers would be detected [10,18,36] . A way to improve on the sensitivity of 85% for CIN 2/3 is to refer women who are hrHPV+ but methylation-negative to retesting for HPV in 1-2 years, which would identify women with persistent infection and reveal most of the remaining CIN2+ cases.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Virtues and Weaknesses of DNA Methylation as a Test for Cervical Cancer Prevention

Lörincz¹

2016

Acta Cytologica

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in cervical tissue, close to 20 have been reported in different studies, and approximately 10 have been repeatedly shown to have elevated methylation in cervical cancers and highgrade CIN (CIN2 and CIN3), most prominently CADM1, EPB41L3, FAM19A4, MAL, PAX1 and SOX1. Obtaining consistent performance data from the literature is quite difficult because most methylation studies used a variety of different assay methodologies and had incomplete and/or biased clinical specimen sets, varying assay thresholds and disparate target gene regions. There have been relatively few validation studies of DNA methylation biomarkers in large population-based screening studies, but an encouraging development more recently is the execution of well-designed studies to test the true performance of the markers in real-world settings. Methylation of HPV genes, especially HPV16, HPV18, HPV31, HPV33 and HPV45, in disease progression has been a major focus of research. Elevated methylation of the HPV16 L1 and L2 open reading frames, in particular, is associated with CIN2, CIN3 and invasive cancer. Essentially all cancers have high levels of methylation for human genes and for driver HPV types, which suggests that quantitative methylation tests may have utility in predicting CIN2 and CIN3 that are likely to progress. It is still early in the process of development of methylation biomarkers, but already they are showing strong promise as a universal and systematic approach to molecular triage, applicable to all Key WordsEpigenetics · DNA methylation · Cervical intraepithelial neoplasia · Cervical cancer · Human papillomavirus · Biomarkers · Triage · Diagnostics · Molecular signature · Classifier · Score Abstract Epigenetics is the study of heritable and non-heritable genetic coding that is additive to information contained within classical DNA base pair sequences. Differential methylation has a fundamental role in the development and outcome of malignancies, chronic and degenerative diseases and aging. DNA methylation can be measured accurately and easily via various molecular methods and has become a key technology for research and healthcare delivery, with immediate roles in the elucidation of disease natural history, diagnostics and drug discovery. This review focuses on cancers of the lower genital tract, for which the most epigenetic information exists. DNA methylation has been proposed as a triage for women infected with human papillomavirus (HPV) and may eventually directly complement or replace HPV screening as a one-step molecular diagnostic and prognostic test. Methylation of human genes is strongly associated with cervical intraepithelial neoplasia (CIN) and cancer. Of the more than 100 human methylation biomarker genes tested so far

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Section: The Interface Of Epigenetics and Geneticsmentioning

confidence: 99%

“…A new and promising triage for hrHPV+ women is DNA methylation testing [1,8,10,17,27,28,30] . Methylation measurement can be done as a simple reflex to the original screening specimen.…”

Section: New Molecular Triage Tests For Hpv-positive Womenmentioning

confidence: 99%

Section: Dna Methylation Testing: Viral or Host Targets?mentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

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Virtues and Weaknesses of DNA Methylation as a Test for Cervical Cancer Prevention

Lörincz¹

2016

Acta Cytologica

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“…Most women might be infected with HPV during their lifetime, but only a small percentage would progress to cervical intraepithelial neoplasia (CIN) grade 3 (CIN3) or cancer [8] . HPV-16 is the most prevalent and persistent HPV, and causes approximately 50-60% of cervical cancer [9] .…”

mentioning

confidence: 99%

Correlation between Methylation of Human Papillomavirus-16 L1 Gene and Cervical Carcinoma in Uyghur Women

Niyazi

Sui²,

Zhu³

et al. 2016

Gynecol Obstet Invest

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Background: This study aims at determining the correlation between CpG methylation in human papillomavirus (HPV)-16 L1 and the persistent infections and development of cervical carcinoma in Uyghur women. Methods: Among the 4,364 Uyghur women, specimens were collected from 145 (3.3%) HPV-16 single infected cases, which were divided into 5 groups: transient infection (n = 32), persistent infection (n = 21, 12 months), cervical intraepithelial neoplasia (CIN) grade 1 (CIN1, n = 21), CIN2-3 (n = 33) and invasive cervical cancer (n = 38) groups. Methylation level in HPV-16 L1 was quantified by pyrosequencing, and values in the prediction and diagnosis of CIN2+ lesions were evaluated with receiver operating characteristic curves. Results: With the progression of the disease, increased methylation was detected at 13 CpG sites, and a high methylation level was associated with the risk of CIN2+. The strongest related site was 6650 (OR 9.89, 95% CI 3.57-27.44). The area under ROC curve (AUC) of methylation at each CpG site to differentiate between CIN2+ and

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Methylation of CpG 5962 in L1 of the human papillomavirus 16 genome as a potential predictive marker for viral persistence: A prospective large cohort study using cervical swab samples

Fertey¹,

Hagmann

Ruscheweyh

et al. 2019

Cancer Medicine

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Several studies have demonstrated that the viral genome can be methylated by the host cell during progression from persistent infection to cervical cancer. The aim of this study was to investigate whether methylation at a specific site could predict the development of viral persistence and whether viral load shows a correlation with specific methylation patterns. HPV16-positive samples from women aged 20-29 years (n = 99) with a follow-up time of 13 years, were included from a Danish cohort comprising 11 088 women. Viral load was measured by real-time PCR and methylation status was determined for 39 CpG sites in the upstream regulatory region (URR), E6/E7, and L1 region of HPV16 by next-generation sequencing. Participants were divided into two groups according to whether they were persistently (≥ 24 months) or transiently HPV16 infected. The general methylation status was significantly different between women with a persistent and women with a transient infection outcome (P = .025). One site located in L1 (nt. 5962) was statistically significantly (P = .00048) different in the methylation status after correction using the Holm-Sidak method (alpha = 0.05). Correlation analyses of samples from HPV16 persistently infected women suggest that methylation is higher although viral load is lower.This study indicates that methylation at position 5962 of the HPV16 genome within the L1 gene might be a predictive marker for the development of a persistent HPV16 infection. K E Y W O R D SBiomarker, DNA Methylation, HPV16, Persistence

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Methylation of viral and host genes and severity of cervical lesions associated with human papillomavirus type 16

Cited by 55 publications

References 33 publications

Virtues and Weaknesses of DNA Methylation as a Test for Cervical Cancer Prevention

Virtues and Weaknesses of DNA Methylation as a Test for Cervical Cancer Prevention

Correlation between Methylation of Human Papillomavirus-16 L1 Gene and Cervical Carcinoma in Uyghur Women

Methylation of CpG 5962 in L1 of the human papillomavirus 16 genome as a potential predictive marker for viral persistence: A prospective large cohort study using cervical swab samples

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