Cytological DNA methylation for cervical cancer screening: a validation set

Linghua Kong; Linhai Wang; Ziyun Wang; Xiaoping Xiao; Yan You; Huanwen Wu; Ming Wu; Pei Liu; Lei Li

doi:10.3389/fonc.2023.1181982

Cytological DNA methylation for cervical cancer screening: a validation set

Front Oncol. 2023 Aug 21:13:1181982. doi: 10.3389/fonc.2023.1181982. eCollection 2023.

Authors

Linghua Kong¹, Linhai Wang², Ziyun Wang², Xiaoping Xiao¹, Yan You³, Huanwen Wu³, Ming Wu¹, Pei Liu², Lei Li¹

Affiliations

¹ Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Beijing, China.
² Department of Technology, Beijing OriginPoly Biotechnology CO., Ltd., Beijing, China.
³ Department of Pathology, Peking Union Medical College Hospital, Beijing, China.

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.

Keywords: DNA methylation; cervical cancer; cervical intraepithelial neoplasia; endometrial carcinoma; high-risk human papillomavirus; validation set.

Grants and funding

This study is supported by the Beijing Science and Technology Projects (No. Z211100002921068), by the Key Research Project of Beijing Natural Science Foundation (No. Z220013), by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2020-PT320-003), by the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2022-I2M-C&T-B-033), by the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-A-117, 2022-PUMCH-B-083, 2022-PUMCH-C-010, 2022-PUMCH-C-022 and 2022-PUMCH-D-003), by the Le Fund (No. KH-2020-LJJ-004, 034 and 035), by the Beijing CSCO Research Fund for Clinical Oncology (No. Y-QL2019-0165 and Y-zai2021/ms-0198) by the China Postdoctoral Science Foundation (No. 2022T150066). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.