{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:21:06Z","timestamp":1789168866408,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"\n Objective<\/jats:title>\n \n Persistent infection with high-risk human papillomavirus (HR-HPV) is the primary cause of cervical cancer (CC). DNA methylation is a promising biomarker for cervical cancer screening. This study aimed to validate the clinical efficacy of a cytological DNA methylation-based ZNF 582 methylation (\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n ) test for triage in detecting cervical intraepithelial neoplasia (CIN) grade 3 or higher (CIN3+) among women with HR-HPV infection.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This case\u2013control study examined 199 women who tested positive for HR-HPV from the colposcopy clinic. The cohort included 15 cases of CC, 37 cases of CIN3, 45 cases of CIN2, 49 cases of CIN1, and 53 normal cases. Using cervical pathology results as a reference, the performance of the\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test for detecting CIN3\u202f+\u202fwas evaluated and compared with liquid-based cytology (LBC) and P16\/Ki67 double stain cytology (DSC).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test showed statistically significant differences in pathological results between CIN2 and CIN3 (\n p<\/jats:italic>\n \u202f&lt;\u202f0.001). The area under the receiver operating characteristic curve (AUC) for distinguishing between &lt;CIN3 and CIN3\u202f+\u202fusing\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test was 0.797 (\n p<\/jats:italic>\n \u202f&lt;\u202f0.001). The\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test demonstrated higher specificity (88.4, 95% CI, 82.1\u201393.1%) compared to cytology (\u2265 atypical squamous cells of undetermined significance; \u2265ASC-US+: 28.6, 95% CI: 21.4\u201336.6%) and P16\/Ki67 DSC (43.5, 95% CI, 35.4\u201352.0%) for detecting CIN3+, establishing it as a superior triage biomarker for women with HR-HPV infection. The Kappa value between the\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test and pathology (&lt;CIN3 vs. CIN3+) exhibited the highest consistency at 0.589 (0.461\u20130.716) when compared to other tests, indicating a strong alignment with pathological findings. In the combined test, the specificity of HPV16\/18 OR\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test was found to be the highest among other combined tests, at 63.3% (95% CI\u202f=\u202f54.9\u201371.1%).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test exhibiting superior triage performance compared to P16\/Ki67 DSC and LBC (ASC-US+). The\n \n ZNF582\n m<\/jats:sup>\n <\/jats:italic>\n test enhances specificity (\n p<\/jats:italic>\n \u202f&lt;\u202f0.001), thereby facilitating the accurate identification of CIN3\u202f+\u202flesions while reducing unnecessary colposcopies. This is particularly crucial in resource-limited settings, where optimizing the accuracy of triage for HR-HPV positive women is essential.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fmed.2025.1687869","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T06:36:19Z","timestamp":1765434979000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["ZNF582 hypermethylation as a highly specific biomarker for triage of high-grade cervical lesions in HR-HPV positive women"],"prefix":"10.3389","volume":"12","author":[{"given":"Yixiang","family":"Lian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shali","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suran","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref1","volume-title":"WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition, WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical 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Dis"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"88","DOI":"10.13390\/j.issn.1672-1861.2025.01.030","article-title":"Guidelines for cervical cancer screening in China II","volume":"26","author":"Li","year":"2025","journal-title":"Chin J Clin Obstet Gynecol"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2024.5374","article-title":"Promising predictive molecular biomarkers for cervical cancer (review)","volume":"53","author":"Lizano","year":"2024","journal-title":"Int J Mol Med"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"8476","DOI":"10.3390\/cimb45100534","article-title":"The role of p16\/Ki67 dual staining in cervical Cancer screening","volume":"45","author":"Dovnik","year":"2023","journal-title":"Curr Issues Mol Biol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1001\/jamaoncol.2018.4270","article-title":"Five-year risk of cervical precancer following p16\/Ki-67 dual-stain triage of HPV-positive 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Gynecol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1002\/ijc.34050","article-title":"DNA methylation testing with S5 for triage of high-risk HPV positive women","volume":"151","author":"Adcock","year":"2022","journal-title":"Int J Cancer"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1097\/LGT.0000000000000830","article-title":"Evaluation of host gene methylation as a triage test for HPV-positive women-a cohort study","volume":"28","author":"Vieira-Baptista","year":"2024","journal-title":"J Low Genit Tract Dis"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"125.e1","DOI":"10.1016\/j.cmi.2020.03.018","article-title":"FAM19A4\/miR124-2 methylation analysis as a triage test for HPV-positive women: cross-sectional and longitudinal data from a Dutch screening cohort","volume":"27","author":"Vink","year":"2021","journal-title":"Clin Microbiol 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Cancer"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1158\/1940-6207.CAPR-25-0029","article-title":"CervicalMethDx: a precision DNA methylation test to identify risk of high-grade intraepithelial lesions in cervical cancer screening algorithms","volume":"18","author":"Palmieri","year":"2025","journal-title":"Cancer Prev Res (Phila)"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1001\/jamainternmed.2019.0306","article-title":"Clinical evaluation of human papillomavirus screening with p16\/Ki-67 dual stain triage in a large organized cervical Cancer screening program","volume":"179","author":"Wentzensen","year":"2019","journal-title":"JAMA Intern Med"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"e0089724","DOI":"10.1128\/spectrum.00897-24","article-title":"Extended HPV genotyping by the BD Onclarity assay: concordance with screening HPV-DNA assays, triage biomarkers, and histopathology in women from the NTCC2 study","volume":"13","author":"De Marco","year":"2025","journal-title":"Microbiol Spectr"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e29271","DOI":"10.1002\/jmv.29271","article-title":"p16\/Ki67 dual stain triage versus cytology in primary human papillomavirus-based cervical cancer screening with limited genotyping","volume":"95","author":"Trzeszcz","year":"2023","journal-title":"J Med Virol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1097\/LGT.0000000000000802","article-title":"Recommendations for use of p16\/Ki67 dual stain for Management of Individuals Testing Positive for human papillomavirus","volume":"28","author":"Clarke","year":"2024","journal-title":"J Low Genit Tract Dis"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ejogrb.2024.09.003","article-title":"Optimization of HPV-positive women triage with p16\/Ki67 dual staining cytology in an organized cervical cancer screening program in the center region of Portugal","volume":"302","author":"Sepodes","year":"2024","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1186\/s12885-024-12920-4","article-title":"Relationship between p16\/ki67 immunoscores and PAX1\/ZNF582 methylation status in precancerous and cancerous cervical lesions in high-risk HPV-positive women","volume":"24","author":"Luo","year":"2024","journal-title":"BMC Cancer"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e075925","DOI":"10.1136\/bmj-2023-075925","article-title":"Untreated cervical intraepithelial neoplasia grade 2 and subsequent risk of cervical cancer: population based cohort study","volume":"383","author":"Lycke","year":"2023","journal-title":"BMJ"}],"container-title":["Frontiers in 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