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Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV\u2010induced host epigenome\u2010wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease\u2010free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)\u2010HPV, a signature reflective of changes in the healthy host epigenome related to high\u2010risk HPV strains (AUC\u00a0=\u00a00.78, 95% CI: 0.72\u20100.85, in nondiseased women). Looking at HPV\u2010associated changes across disease development, HPV\u2010infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1\/2, CIN1\/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID\u2010HPV index, indicating the WID\u2010HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID\u2010HPV is positively associated with apoptosis (<jats:italic>\u03c1<\/jats:italic>\u00a0=\u00a00.48;<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.001) and negatively associated with epigenetic replicative age (<jats:italic>\u03c1<\/jats:italic>\u00a0=\u00a0\u22120.43;<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.001). Taken together, our data suggest the WID\u2010HPV captures a clearance response associated with apoptosis of HPV\u2010infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer.<\/jats:p>","DOI":"10.1002\/ijc.34477","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T01:59:52Z","timestamp":1677031192000},"page":"2321-2330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>HPV<\/scp>\u2010induced host epigenetic reprogramming is lost upon progression to high\u2010grade cervical intraepithelial neoplasia"],"prefix":"10.1002","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1572-498X","authenticated-orcid":false,"given":"Chiara","family":"Herzog","sequence":"first","affiliation":[{"name":"European Translational Oncology Prevention and Screening (EUTOPS) Institute Universit\u00e4t Innsbruck Hall in Tirol Tirol Austria"},{"name":"Institute for Biomedical Aging Research Universit\u00e4t Innsbruck Innsbruck 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