HPV33 DNA methylation measurement improves cervical pre-cancer risk estimation of an HPV16, HPV18, HPV31 and \textit{EPB41L3} methylation classifier

Brentnall, Adam R.; Vasiljević, Nataša; Scibior‐Bentkowska, Dorota; Cadman, Louise; Austin, Janet; Cuzick, Jack; Lörincz, Attila T.

doi:10.3233/cbm-150507

Cited by 49 publications

(80 citation statements)

References 23 publications

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“…We validated a DNA methylation classifier of CIN2+ histology, using hrHPV‐positive women from a UK screening group. The AUC obtained in this study was 0.78 (95% CI 0.69–0.88) compared with 0.82 (95% CI 0.80–0.84) in the colposcopy referral sample originally used to develop the classifier . The S5 classifier is a multibiomarker panel composed of a human gene EPB41L3 and the late regions of the four clinically most important HPV types: HPV16, HPV18, HPV31 and HPV33 .…”

Section: Discussionmentioning

confidence: 76%

“…The S5 classifier is a multibiomarker panel composed of a human gene EPB41L3 and the late regions of the four clinically most important HPV types: HPV16, HPV18, HPV31 and HPV33 . S5 performed significantly better than an alternative methylation classifier (S4) that lacked measurement of HPV33 . We further observed that the HPV33 component was more important than either HPV18 or HPV31 (Table ).…”

Section: Discussionmentioning

confidence: 84%

“…The main objective of this study was to assess the use of S5 as a triage test to identify CIN2+ in hrHPV‐positive women from a London screening cohort, and to compare it with HPV16/18 genotyping. The secondary aim was to compare the performance of S5 with an earlier risk score (S4) that does not use HPV33 methylation …”

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confidence: 99%

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Validation of a DNA methylation HPV triage classifier in a screening sample

Lörincz

Brentnall

Scibior‐Bentkowska

et al. 2016

Intl Journal of Cancer

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136

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High‐risk human papillomavirus (hrHPV) DNA tests have excellent sensitivity for detection of cervical intraepithelial neoplasia 2 or higher (CIN2+). A drawback of hrHPV screening, however, is modest specificity. Therefore, hrHPV‐positive women might need triage to reduce adverse events and costs associated with unnecessary colposcopy. We compared the performance of HPV16/18 genotyping with a predefined DNA methylation triage test (S5) based on target regions of the human gene EPB41L3, and viral late gene regions of HPV16, HPV18, HPV31 and HPV33. Assays were run using exfoliated cervical specimens from 710 women attending routine screening, of whom 38 were diagnosed with CIN2+ within a year after triage to colposcopy based on cytology and 341 were hrHPV positive. Sensitivity and specificity of the investigated triage methods were compared by McNemar's test. At the predefined cutoff, S5 showed better sensitivity than HPV16/18 genotyping (74% vs 54%, P = 0.04) in identifying CIN2+ in hrHPV‐positive women, and similar specificity (65% vs 71%, P = 0.07). When the S5 cutoff was altered to allow equal sensitivity to that of genotyping, a significantly higher specificity of 91% was reached (P < 0.0001). Thus, a DNA methylation test for the triage of hrHPV‐positive women on original screening specimens might be a valid approach with better performance than genotyping.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 84%

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Validation of a DNA methylation HPV triage classifier in a screening sample

Lörincz

Brentnall

Scibior‐Bentkowska

et al. 2016

Intl Journal of Cancer

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136

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“…S2), methylation of this region was assayed in the main study because of the importance of HPV18 as a carcinogenic HPV. To these assays we added biomarkers in the L1 region of HPV31 and the L2 region of HPV33, which were validated as informative in different studies …”

Section: Resultsmentioning

confidence: 99%

Molecular progression to cervical precancer, epigenetic switch or sequential model?

Nedjai¹,

Reuter²,

Ahmad³

et al. 2018

Intl Journal of Cancer

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The evolution of precancerous cervical lesions is poorly understood. A widely held model of cervical intraepithelial neoplasia grade 3 (CIN3) development is sequential progression from normal through CIN1 and CIN2 to CIN3. Another hypothesis, the “molecular switch” model, postulates that CIN3 can evolve directly from human papillomavirus (HPV)‐infected normal epithelium without progressing through CIN1 and CIN2. To shed light on this process, we compared DNA methylation of selected human biomarkers and HPV types in two groups of CIN1: CIN1 that were near or adjacent to CIN3 (adjacent‐CIN1) and CIN1 that were the principal lesions with no CIN3 detected (principal‐CIN1). 354 CIN (CIN1 and CIN3) and normal tissue areas were dissected and typed for HPV from 127 women who underwent loop electrosurgical excision procedures (LEEP). Methylation of genes EPB41L3 and the viral regions of HPV16‐L1/L2, HPV18‐L2, HPV31‐L1, and HPV33‐L2 were determined by a highly accurate quantitative pyrosequencing of bisulfite converted DNA. There was a significant trend of increased methylation with disease grade comparing normal to CIN1 and CIN3 (p < 0.0001). Adjacent‐CIN1 predominantly shared the same HPV types as the CIN3, however, methylation differed substantially between adjacent‐CIN1 and CIN3 (p = 0.008). In contrast diagnostically principal‐CIN1 had an indistinguishable methylation distribution compared to adjacent‐CIN1 (EPB41L3: p = 0.49; HPVme‐All: p = 0.11). Our results suggest that progression from normal epithelium to CIN1 or CIN3 is usually promoted by the same HPV type but occurs via distinct DNA epigenotypes, thus favoring the “molecular switch” model.

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“…can be associated with cervical carcinogenesis (41–47). Several Mycoplasma species infect eukaryotic cells, where they activate genes and have been associated with malignant transformations (14, 17, 48, 49).…”

Section: Discussionmentioning

confidence: 99%

Mycoplasma hominis and Mycoplasma genitalium in the Vaginal Microbiota and Persistent High-Risk Human Papillomavirus Infection

Adebamowo

Zella

et al. 2017

Front. Public Health

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BackgroundRecent studies have suggested that the vaginal microenvironment plays a role in persistence of high-risk human papillomavirus (hrHPV) infection and thus cervical carcinogenesis. Furthermore, it has been shown that some mycoplasmas are efficient methylators and may facilitate carcinogenesis through methylation of hrHPV and cervical somatic cells. We examined associations between prevalence and persistence of Mycoplasma spp. in the vaginal microbiota, and prevalent as well as persistent hrHPV infections.MethodsWe examined 194 Nigerian women who were tested for hrHPV infection using SPF25/LiPA10 and we identified Mycoplasma genitalium and Mycoplasma hominis in their vaginal microbiota established by sequencing the V3–V4 hypervariable regions of the 16S rRNA gene. We defined the prevalence of M. genitalium, M. hominis, and hrHPV based on positive result of baseline tests, while persistence was defined as positive results from two consecutive tests. We used exact logistic regression models to estimate associations between Mycoplasma spp. and hrHPV infections.ResultsThe mean (SD) age of the study participants was 38 (8) years, 71% were HIV positive, 30% M. genitalium positive, 45% M. hominis positive, and 40% hrHPV positive at baseline. At follow-up, 16% of the women remained positive for M. genitalium, 30% for M. hominis, and 31% for hrHPV. There was a significant association between persistent M. hominis and persistent hrHPV (OR 8.78, 95% CI 1.49–51.6, p 0.01). Women who were positive for HIV and had persistent M. hominis had threefold increase in the odds of having persistent hrHPV infection (OR 3.28, 95% CI 1.31–8.74, p 0.008), compared to women who were negative for both.ConclusionWe found significant association between persistent M. hominis in the vaginal microbiota and persistent hrHPV in this study, but we could not rule out reverse causation. Our findings need to be replicated in larger, longitudinal studies and if confirmed, could have important diagnostic and therapeutic implications.

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HPV33 DNA methylation measurement improves cervical pre-cancer risk estimation of an HPV16, HPV18, HPV31 and \textit{EPB41L3} methylation classifier

Cited by 49 publications

References 23 publications

Validation of a DNA methylation HPV triage classifier in a screening sample

Validation of a DNA methylation HPV triage classifier in a screening sample

Molecular progression to cervical precancer, epigenetic switch or sequential model?

Mycoplasma hominis and Mycoplasma genitalium in the Vaginal Microbiota and Persistent High-Risk Human Papillomavirus Infection

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