Dataset Information

Cytological DNA methylation for cervical cancer screening: a validation set.

ABSTRACT:

Background

In a previous training set with a case-controlled design, cutoff values for host EPB41L3 and JAM3 gene methylation were obtained for the detection of cervical intraepithelial neoplasia (CIN) 2 or more severe lesions (CIN2+). This validation trial was conducted to evaluate the role of DNA methylation in screening for CIN2+ by cervical cytology among unselected participants.

Methods

From June 1, 2019, to September 1, 2019, in our study center, we collected liquid-based samples from cervical swabs for methylation assays and hrHPV testing in eligible patients. The primary endpoint was the diagnostic accuracy of DNA methylation and hrHPV genotyping for CIN2+ according to confirmed histology results.

Results

Among 307 participants, compared with hrHPV testing, the methylation assay for CIN2+ had lower sensitivity (68.7% versus 86.1%, p=0.002) but higher specificity (96.7% versus 0.696, p<0.001). The methylation assay also had favorable sensitivity and specificity in patients with negative hrHPV testing (56.3% and 96.9%) and in patients with cervical adenocarcinoma (73.7% and 92.7%). DNA methylation had higher specificity than the hrHPV assay (100.0% versus 44.4%, p<0.001) for identifying residual CIN2+ in patients without residual lesions. Positive cervical DNA methylation was associated with a diagnostic probability of endometrial carcinoma (odds ratio 15.5 [95% confidence interval 4.1-58.6]) but not of ovarian epithelial carcinoma (1.4 [0.3-6.5]).

Conclusions

The host EPB41L3 and JAM3 gene methylation assay in cervical cytology had favorable diagnostic accuracy for CIN2+ and was highly specific for residual CIN2+ lesions The methylation assay is a promising triage tool in hrHPV+ women, or even an independent tool for cervical cancer screening. The methylation status in cervical cytology could also serve as a prognostic biomarker. Its role in detecting endometrial carcinomas is worthy of further exploration.

SUBMITTER: Kong L

PROVIDER: S-EPMC10475939 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Cytological DNA methylation for cervical cancer screening: a validation set.

Kong Linghua L Wang Linhai L Wang Ziyun Z Xiao Xiaoping X You Yan Y Wu Huanwen H Wu Ming M Liu Pei P Li Lei L

Frontiers in oncology 20230821

<h4>Background</h4>In a previous training set with a case-controlled design, cutoff values for host <i>EPB41L3</i> and <i>JAM3</i> gene methylation were obtained for the detection of cervical intraepithelial neoplasia (CIN) 2 or more severe lesions (CIN2+). This validation trial was conducted to evaluate the role of DNA methylation in screening for CIN2+ by cervical cytology among unselected participants.<h4>Methods</h4>From June 1, 2019, to September 1, 2019, in our study center, we collected l ...[more]

PMID: 37671063

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Project description:BACKGROUND:Ovarian cancer (OC) is the most lethal gynecological cancer, worldwide, largely due to its vague and nonspecific early stage symptoms, resulting in most tumors being found at advanced stages. Moreover, due to its relative rarity, there are currently no satisfactory methods for OC screening, which remains a controversial and cost-prohibitive issue. Here, we demonstrate that Papanicolaou test (Pap test) cervical scrapings, instead of blood, can reveal genetic/epigenetic information for OC detection, using specific and sensitive DNA methylation biomarkers. RESULTS:We analyzed the methylomes of tissues (50 OC tissues versus 6 normal ovarian epithelia) and cervical scrapings (5 OC patients versus 10 normal controls), and integrated public methylomic datasets, including 79 OC tissues and 6 normal tubal epithelia. Differentially methylated genes were further classified by unsupervised hierarchical clustering, and each candidate biomarker gene was verified in both OC tissues and cervical scrapings by either quantitative methylation-specific polymerase chain reaction (qMSP) or bisulfite pyrosequencing. A risk-score by logistic regression was generated for clinical application. One hundred fifty-one genes were classified into four clusters, and nine candidate hypermethylated genes from these four clusters were selected. Among these, four genes fulfilled our selection criteria and were validated in training and testing set, respectively. The OC detection accuracy was demonstrated by area under the receiver operating characteristic curves (AUCs) in 0.80-0.83 of AMPD3, 0.79-0.85 of AOX1, 0.78-0.88 of NRN1, and 0.82-0.85 of TBX15. From this, we found OC-risk score, equation generated by logistic regression in training set and validated an OC-associated panel comprising AMPD3, NRN1, and TBX15, reaching a sensitivity of 81%, specificity of 84%, and OC detection accuracy of 0.91 (95% CI, 0.82-1) in testing set. CONCLUSIONS:Ovarian cancer detection from cervical scrapings is feasible, using particularly promising epigenetic biomarkers such as AMPD3/NRN1/TBX15. Further validation is warranted.

Project description:BackgroundCompared with women who are human immunodeficiency virus (HIV) negative, women with human immunodeficiency virus (WWH) have a higher human papillomavirus (HPV) prevalence and increased cervical cancer risk, emphasizing the need for effective cervical cancer screening in this population. The present study aimed to validate methylation markers ASCL1 and LHX8 for primary screening in a South African cohort of WWH.MethodsIn this post hoc analysis within the DIAgnosis in Vaccine And Cervical Cancer Screen (DiaVACCS) study, a South African observational multicenter cohort study, cervical scrape samples from 411 HIV-positive women were analyzed for hypermethylation of ASCL1 and LHX8 genes, HPV DNA, and cytology. Sensitivities, specificities, and positive and negative predictive values of primary methylation-based, HPV-based and cytology-based screening were calculated for the detection of cervical intraepithelial neoplasia of grade 3 or higher.ResultsSingle markers ASCL1 and LHX8 resulted in a good performance for the detection of cervical intraepithelial neoplasia of grade 3 or higher, with sensitivities of 85.9% (95% confidence interval [CI], 78.2%-93.6%) and 89.7% (83.0%-96.5%), respectively, and specificities of 72.9% (67.3%-78.5%) and 75.0% (69.5%-80.5%). Combining markers ASCL1 and LHX8 resulted in a lower sensitivity compared with HPV testing (84.6% vs 93.6%, respectively; ratio, 0.90 [95% CI, .82-.99]) and a higher specificity (86.7% vs 78.3%; ratio 1.11 [1.02-1.20]) and reduced the referral rate from 46.8% to 33.4%. ASCL1/LHX8 methylation had a significantly higher sensitivity than cytology (threshold, high-grade intraepithelial squamous lesion or worse), (84.6% vs 74.0%, respectively; ratio, 1.16 [95% CI, 1.01-1.32]) and similar specificity (86.7% vs 91.0%; ratio, 0.95 [.90-1.003]).ConclusionsOur results validate the accuracy of ASCL1/LHX8 methylation analysis for primary screening in WWH, which offers a full-molecular alternative to cytology- or HPV-based screening, without the need for additional triage testing.

Dataset Information

Cytological DNA methylation for cervical cancer screening: a validation set.

Background

Methods

Results

Conclusions

Publications

Cytological DNA methylation for cervical cancer screening: a validation set.

Similar Datasets

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