Associations of human gene EPB41L3 DNA methylation and cervical intraepithelial neoplasia in women living with HIV-1 in Africa

Kelly, Helen; Chikandiwa, Admire; Warman, Rhian; Segondy, Michel; Sawadogo, Bernard; Vasiljević, Nataša; Didelot, Marie-Noëlle; Méda, Nicolas; Weiss, Helen A.; Delany‐Moretlwe, Sinead; Mayaud, Philippe; Lörincz, Attila T.

doi:10.1097/qad.0000000000001932

Cited by 21 publications

(30 citation statements)

References 46 publications

(63 reference statements)

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“…The expression of DNA methylation in any of both genes is defined "positive." HPV 11,18,33,51,52,56,59, and 66, respectively) no more than 36 were recorded as positive. A positive hrHPV plus methylation status indicates hrHPV positivity as well as methylation positivity for EPB41L3 or JAM3 (or both).…”

Section: Dna Methylation Testingmentioning

confidence: 99%

“…Multiple panels consisting of dozens of candidate host genes, virus genes or both, as well as various combinations, have been utilized as classifiers [14]. A number of studies have explored the role of a panel including EPB41L3 [15][16][17][18][19][20][21][22][23][24], JAM3 [25,26], or both [7,[27][28][29][30][31] in the screening or triage of HSIL and/or cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation for cervical cancer screening: a training set in China

Kong

Wang²,

Wang³

et al. 2020

Clin Epigenet

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Background: Despite rapid improvements in DNA methylation tools for cervical cancer screening, few robust, exploratory studies have been performed using the combination of two host genes, EPB41L3 and JAM3, newly developed assays. Methods: A review of abnormal liquid-based cytology and/or high-risk human papillomavirus (hrHPV) data from outpatient clinics in the study center from March 2018 to March 2019 was performed. Eligible patients with definitive histological pathology results were included, and their residual cytology samples were assessed for EPB41L3 and JAM3 methylation. The diagnostic accuracies of various screening strategies for definitive pathology and for cervical intraepithelial neoplasia (CIN) 2 or more severe lesions (CIN2+) were compared. Results: In total, 306 patients were successfully tested; 301 cases with cervical histological pathology were included in the final analysis, including 118 (39.2%) and 183 (60.8%) cases of inflammation/CIN1 and CIN2+, respectively. Regarding CIN2+ detection, methylation status and hrHPV plus methylation had similar positive predictive values (0.930 and 0.954, respectively, p = 0.395). Additionally, hrHPV, methylation, and hrHPV plus methylation had similar negative predictive values (0.612, 0.679, and 0.655, p = 0.677) that were significantly higher than that of cytology alone (0.250, p values 0.012, 0.001, and 0.001, respectively). For 49 cases with negative hrHPV results, positive methylation alone was able to differentiate CIN2+ from inflammation/CIN1. Conclusions: Methylation of both EPB41L3 and JAM3 is an accurate and feasible screening method for CIN2+.

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Section: Dna Methylation Testingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA methylation for cervical cancer screening: a training set in China

Kong

Wang²,

Wang³

et al. 2020

Clin Epigenet

View full text Add to dashboard Cite

show abstract

“…A number of studies have explored the role of a panel that includes EPB41L3, [15][16][17][18][19][20][21][22][23][24] JAM3, [25] or both [7,[26][27][28][29][30] for the screening or triage of HSIL and/or cervical cancer. In this validation trial, the performance of DNA methylation assessment based on the EPB41L3 and JAM3 genes was similar to that of our training set, [14] and the assessment showed favorable results in identifying CIN2+ or ADC .…”

Section: Discussionmentioning

confidence: 99%

“…No matter whether the patients previously received hrHPV testing or not, hrHPV genotyping was uniformly performed with TaqMan-based technology using an ABI 7500 Real Time Fluorescence Quantitative PCR system (Life Tech, USA) or a Stratagene Mx3000p Fluorescence Quantitative PCR system (Stratagene, USA) with an HPV nucleic acid genotyping diagnostic kit (Real time Fluorescent PCR) (Beijing SinoMDgene Technology Co., Ltd, China). The diagnostic kit detects a pooled result for hrHPV types, including HPV 16,18,31,33,45,52,6,11,35,51,39,59,68,56,58, and 66, with type-speci c probes.…”

Section: Collection and Assays Of Study Materialsmentioning

confidence: 99%

DNA methylation for cervical cancer screening: A validation trial in China

Kong¹,

Wang²,

Wang³

et al. 2020

Preprint

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Background Based on published results from a training set, EPB41L3 and JAM3 gene methylation status had favorite results compared with high-risk human papillomavirus (hrHPV) testing. This validation trial evaluated the DNA methylation status and genotyping of hrHPV in unselected patients with gynecologic diseases.Methods This study enrolled all patients in the study center from June 1, 2019 to September 1, 2019. Liquid-based samples were collected from cervical swabs for methylation assays and hrHPV testing one day before surgery. The primary endpoint was the diagnostic accuracies of DNA methylation and hrHPV genotyping for cervical intraepithelial neoplasia (CIN) 2 or more severe lesions (CIN2+).Results In total, 307 patients were included in the final analysis, with a median age of 46 years. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the methylation assay for CIN2+ were 68.7%, 96.7%, 0.933 and 0.712, respectively, and the methylation assay achieved similar diagnostic accuracies to those in the training set and to hrHPV testing. Even in patients with negative hrHPV results, DNA methylation was significantly able to identify CIN2+ (odds ratio 39.857, 95% confidence interval 7.137-222.577). The methylation assay was sensitive for CIN2/3 and cervical squamous cell carcinoma without residual lesions and was not positive in this context.Conclusion For the diagnosis of cervical adenocarcinoma, methylation assessment, hrHPV testing and their combination had favorable results in all subtypes.

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“…So far, a limited number of studies on host cell DNA methylation have included WLHIV [ 27 , 31 , 36 , 37 , 38 , 39 ]. We previously showed that WLHIV without cervical disease have increased methylation levels of host cell genes compared with HIV-uninfected women without cervical disease [ 27 , 31 ], which might make them more susceptible to HPV-induced cervical neoplasia.…”

Section: Discussionmentioning

confidence: 99%

HPV16-Related Cervical Cancers and Precancers Have Increased Levels of Host Cell DNA Methylation in Women Living with HIV

Kremer

Zummeren

Heideman

et al. 2018

IJMS

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Data on human papillomavirus (HPV) type-specific cervical cancer risk in women living with human immunodeficiency virus (WLHIV) are needed to understand HPV–HIV interaction and to inform prevention programs for this population. We assessed high-risk HPV type-specific prevalence in cervical samples from 463 WLHIV from South Africa with different underlying, histologically confirmed stages of cervical disease. Secondly, we investigated DNA hypermethylation of host cell genes ASCL1, LHX8, and ST6GALNAC5, as markers of advanced cervical disease, in relation to type-specific HPV infection. Overall, HPV prevalence was 56% and positivity increased with severity of cervical disease: from 28.0% in cervical intraepithelial neoplasia (CIN) grade 1 or less (≤CIN1) to 100% in invasive cervical cancer (ICC). HPV16 was the most prevalent type, accounting for 9.9% of HPV-positive ≤CIN1, 14.3% of CIN2, 31.7% of CIN3, and 45.5% of ICC. HPV16 was significantly more associated with ICC and CIN3 than with ≤CIN1 (adjusted for age, ORMH 7.36 (95% CI 2.33–23.21) and 4.37 (95% CI 1.81–10.58), respectively), as opposed to non-16 high-risk HPV types. Methylation levels of ASCL1, LHX8, and ST6GALNAC5 in cervical scrapes of women with CIN3 or worse (CIN3+) associated with HPV16 were significantly higher compared with methylation levels in cervical scrapes of women with CIN3+ associated with non-16 high-risk HPV types (p-values 0.017, 0.019, and 0.026, respectively). When CIN3 and ICC were analysed separately, the same trend was observed, but the differences were not significant. Our results confirm the key role that HPV16 plays in uterine cervix carcinogenesis, and suggest that the evaluation of host cell gene methylation levels may monitor the progression of cervical neoplasms also in WLHIV.

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Associations of human gene EPB41L3 DNA methylation and cervical intraepithelial neoplasia in women living with HIV-1 in Africa

Abstract: Methylation of EPB41L3 DNA is elevated among WLHIV with CIN2+ and independently associated with lower CD4 count and ART use.

Cited by 21 publications

References 46 publications

DNA methylation for cervical cancer screening: a training set in China

DNA methylation for cervical cancer screening: a training set in China

DNA methylation for cervical cancer screening: A validation trial in China

HPV16-Related Cervical Cancers and Precancers Have Increased Levels of Host Cell DNA Methylation in Women Living with HIV

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