{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:59:11Z","timestamp":1792112351441,"version":"4.4.0"},"reference-count":31,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T00:00:00Z","timestamp":1716768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)\u2010vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false\u2010positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case\u2013control study, 9242 women who received the three\u2010dose HPV16\/18\u2010vaccine at ages 12\u201315 or 18 in a community\u2010randomized trial were included. Subsequently, they were re\u2010randomized for either frequent or infrequent cervical cancer screening trials. Over a 15\u2010year post\u2010vaccination follow\u2010up until 2022, 17 high\u2010grade squamous intraepithelial lesion (HSIL) and 15 low\u2010grade (LSIL) cases were identified at the 25\u2010year screening round, alongside 371 age and community\u2010matched HPV16\/18\u2010vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16\/18\/31\/33) and host\u2010cell genes (<jats:italic>EPB41L3<\/jats:italic>, <jats:italic>FAM19A4<\/jats:italic>, and <jats:italic>miR124\u20102)<\/jats:italic> was measured, along with HPV\u2010genotyping. No HPV16\/18 HSIL cases were observed. The predominant HPV\u2010genotypes were HPV52 (29.4%), HPV59\/HPV51\/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host\u2010cell genes between the LSIL\/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and <jats:italic>EPB41L3<\/jats:italic> (<jats:italic>p<\/jats:italic> value\u2009=\u2009.0001). HPV\u2010vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV\u2010vaccinated women and its implications for management.<\/jats:p>","DOI":"10.1002\/ijc.35044","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T13:54:08Z","timestamp":1716818048000},"page":"1549-1557","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Low methylation marker levels among human papillomavirus\u2010vaccinated women with cervical high\u2010grade squamous intraepithelial lesions"],"prefix":"10.1002","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1172-363X","authenticated-orcid":false,"given":"Karolina","family":"Louvanto","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health Technology Tampere University  Tampere Finland"},{"name":"Department of Obstetrics and Gynecology Tampere University Hospital  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-0297","authenticated-orcid":false,"given":"Lisanne","family":"Verhoef","sequence":"additional","affiliation":[{"name":"Pathology Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Imaging and Biomarkers Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0813-7031","authenticated-orcid":false,"given":"Ville","family":"Pimenoff","sequence":"additional","affiliation":[{"name":"Unit of Cervical Cancer Elimination, Department of Clinical Science, Intervention and Technology CLINTEC, Karolinska Institute  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiina","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology Tampere University  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siiri","family":"Lepp\u00e4l\u00e4","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology Tampere University  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Lagheden","sequence":"additional","affiliation":[{"name":"Unit of Cervical Cancer Elimination, Department of Clinical Science, Intervention and Technology CLINTEC, Karolinska Institute  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9065-4734","authenticated-orcid":false,"given":"Penelope","family":"Gray","sequence":"additional","affiliation":[{"name":"Unit of Cervical Cancer Elimination, Department of Clinical Science, Intervention and Technology CLINTEC, Karolinska Institute  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Scibior\u2010Bentkowska","sequence":"additional","affiliation":[{"name":"Centre for Cancer Screening, Prevention and Early Detection (SPED), Wolfson Institute of Population Health Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Sumiec","sequence":"additional","affiliation":[{"name":"Centre for Cancer Screening, Prevention and Early Detection (SPED), Wolfson Institute of Population Health Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pekka","family":"Nieminen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Helsinki University Hospital  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8588-6506","authenticated-orcid":false,"given":"Joakim","family":"Dillner","sequence":"additional","affiliation":[{"name":"Unit of Cervical Cancer Elimination, Department of Clinical Science, Intervention and Technology CLINTEC, Karolinska Institute  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Berkhof","sequence":"additional","affiliation":[{"name":"Epidemiology and Data Science Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J. 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