{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T22:02:27Z","timestamp":1791756147525,"version":"4.3.4"},"reference-count":42,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T00:00:00Z","timestamp":1530576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C569\/A10404"],"award-info":[{"award-number":["C569\/A10404"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:p>The evolution of precancerous cervical lesions is poorly understood. A widely held model of cervical intraepithelial neoplasia grade 3 (CIN3) development is sequential progression from normal through CIN1 and CIN2 to CIN3. Another hypothesis, the \u201cmolecular switch\u201d model, postulates that CIN3 can evolve directly from human papillomavirus (HPV)\u2010infected normal epithelium without progressing through CIN1 and CIN2. To shed light on this process, we compared DNA methylation of selected human biomarkers and HPV types in two groups of CIN1: CIN1 that were near or adjacent to CIN3 (adjacent\u2010CIN1) and CIN1 that were the principal lesions with no CIN3 detected (principal\u2010CIN1). 354 CIN (CIN1 and CIN3) and normal tissue areas were dissected and typed for HPV from 127 women who underwent loop electrosurgical excision procedures (LEEP). Methylation of genes <jats:italic>EPB41L3<\/jats:italic> and the viral regions of HPV16\u2010L1\/L2, HPV18\u2010L2, HPV31\u2010L1, and HPV33\u2010L2 were determined by a highly accurate quantitative pyrosequencing of bisulfite converted DNA. There was a significant trend of increased methylation with disease grade comparing normal to CIN1 and CIN3 (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001). Adjacent\u2010CIN1 predominantly shared the same HPV types as the CIN3, however, methylation differed substantially between adjacent\u2010CIN1 and CIN3 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.008). In contrast diagnostically principal\u2010CIN1 had an indistinguishable methylation distribution compared to adjacent\u2010CIN1 (<jats:italic>EPB41L3: p<\/jats:italic>\u00a0=\u00a00.49; HPVme\u2010All: <jats:italic>p<\/jats:italic>\u00a0=\u00a00.11). Our results suggest that progression from normal epithelium to CIN1 or CIN3 is usually promoted by the same HPV type but occurs via distinct DNA epigenotypes, thus favoring the \u201cmolecular switch\u201d model.<\/jats:p>","DOI":"10.1002\/ijc.31549","type":"journal-article","created":{"date-parts":[[2018,4,21]],"date-time":"2018-04-21T10:20:50Z","timestamp":1524306050000},"page":"1720-1730","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Molecular progression to cervical precancer, epigenetic switch or sequential model?"],"prefix":"10.1002","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8711-4577","authenticated-orcid":false,"given":"Belinda","family":"Nedjai","sequence":"first","affiliation":[{"name":"Barts and the London School of Medicine, Charterhouse Square Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine  London EC1M 6BQ United 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