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Effective screening programs are critical to reduce the incidence and mortality. High\u2010risk HPV (hr\u2010HPV) testing as primary screening tool discloses high sensitivity but suboptimal specificity. Adequate triage tests to reduce unnecessary colposcopy referrals and overdiagnosis\/overtreatment are crucial. Hence, we aimed to validate a panel of DNA methylation\u2010based markers as triage test for women hr\u2010HPV+ in the population\u2010based Regional Cervical Cancer Screening Program of Northern Portugal. Firstly, <jats:italic>CADM1<\/jats:italic>, <jats:italic>MAL<\/jats:italic>, <jats:italic>FAM19A4<\/jats:italic> and <jats:italic>hsa\u2010miR124\u20102<\/jats:italic> promoter methylation levels were assessed by multiplex QMSP in a testing set of 402 FFPE tissue samples (159 normal samples and 243 cervical lesions, including 39 low\u2010grade intraepithelial squamous lesions [LSIL], 59 high\u2010grade intraepithelial squamous lesions [HSIL] and 145 cancerous lesions). Then, preliminary validation was performed in 125 hr\u2010HPV+ cervical scrapes (including 59 normal samples, 30 LSIL, 34 HSIL and 2 cancerous lesions). Higher <jats:italic>MAL<\/jats:italic><jats:sup><jats:italic>me<\/jats:italic><\/jats:sup>, <jats:italic>FAM19A4<\/jats:italic><jats:sup><jats:italic>me<\/jats:italic><\/jats:sup> and <jats:italic>hsa\u2010miR124\u20102<\/jats:italic><jats:sup><jats:italic>me<\/jats:italic><\/jats:sup> methylation levels were disclosed in histological HSIL or worse (HSIL+) in testing set. Individually, markers depicted over 86% specificity for HSIL+ detection. In validation set, all these genes significantly differed between histological HSIL+ and low\u2010grade squamous intraepithelial lesions or less. In combination, these markers reached 74% specificity and 61% sensitivity for identification of histological HSIL+. We concluded that host gene methylation might constitute a useful referral triage tool of hr\u2010HPV+ women enrolled in the Cervical Cancer Screening Program of Northern Portugal.<\/jats:p>","DOI":"10.1002\/ijc.33778","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T14:41:27Z","timestamp":1630334487000},"page":"1916-1925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Performance of <scp>DNA<\/scp> methylation\u2010based biomarkers in the cervical cancer screening program of northern Portugal: A feasibility study"],"prefix":"10.1002","volume":"149","author":[{"given":"Sofia","family":"Salta","sequence":"first","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group, Research Center of IPO Porto (CI\u2010IPOP)\/RISE@CI\u2010IPOP (Health Research Network) Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC)  Porto Portugal"},{"name":"Doctoral Program in Molecular Pathology and Genetics School of Medicine and Biomedical Sciences\u2010University of Porto (ICBAS\u2010UP)  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Maia\u2010Mo\u00e7o","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; 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