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In this epigenome\u2010wide association study (EWAS) we explore differential DNA methylation signatures associated with CIN (cervical intraepithelial neoplasia) grade 3 and cervical cancer to better understand potential drivers and biomarkers of cervical carcinogenesis. 247 women were recruited between 2014 and 2020 (<jats:italic>N<\/jats:italic>\u2009=\u2009119 benign, <jats:italic>N<\/jats:italic>\u2009=\u200974 CIN3\/CGIN [cervical glandular intraepithelial neoplasia] and <jats:italic>N<\/jats:italic>\u2009=\u200954 cancer). Methylation signatures were obtained from exfoliated cervical cells and sequenced using the Illumina 850\u2009k array. Logistic regression and conditional analyses were used to test for independent associations between Cytosine\u2010phosphate\u2010Guanine (CpG) sites and case\u2013control status, with adjustment for batch, chip, age, and human papillomavirus (HPV) status. 409 CpG sites were strongly associated with CIN3\/cancer (<jats:italic>p<\/jats:italic>\u2010value &lt;5\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>). Following conditional analysis, two CpG sites located in <jats:italic>PAX1<\/jats:italic> (cg16767801) and <jats:italic>NREP\u2010AS1<\/jats:italic> genes (cg23642047) were independently associated with case status, yielding an area under the curve (AUC) of 0.92 (AUC\u2009=\u20090.97 for invasive disease). In a validation dataset (CIN3 only) <jats:italic>PAX1\/NREP\u2010AS1<\/jats:italic> yielded a combined AUC of 0.77. Methylation markers offer promise for use in cervical screening, particularly as triage tests and self\u2010sampling. We have identified a novel combined methylation marker that offers a high accuracy for the detection of CIN3 or worse.<\/jats:p>","DOI":"10.1002\/ijc.35406","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T03:44:41Z","timestamp":1741751081000},"page":"305-316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["DNA methylation signatures of cervical pre\u2010invasive and invasive disease: An epigenome\u2010wide association study"],"prefix":"10.1002","volume":"157","author":[{"given":"Sarah J.","family":"Bowden","sequence":"first","affiliation":[{"name":"Department of Metabolism, Digestion and Reproduction IRDB, Faculty of Medicine, Imperial College London  London UK"},{"name":"Department of Surgery &amp; Cancer IRDB, Faculty of Medicine, Imperial College London  London UK"},{"name":"West London Gynaecology Cancer Centre, Hammersmith Hospital, Imperial Healthcare NHS Trust  London 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