{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:27:57Z","timestamp":1791959277971,"version":"4.3.4"},"reference-count":26,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["11337"],"award-info":[{"award-number":["11337"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["847845"],"award-info":[{"award-number":["847845"]}],"id":[{"id":"10.13039\/501100000780","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":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Methylation of host\u2010cell deoxyribonucleic acid (DNA) has been proposed as a promising biomarker for triage of high\u2010risk (hr) human papillomavirus (HPV) positive women at screening. Our study aims to validate recently identified host\u2010cell DNA methylation markers for triage in an hrHPV\u2010positive cohort derived from primary HPV\u2010based cervical screening in The Netherlands. Methylation markers <jats:italic>ASCL1, LHX8, ST6GALNAC5, GHSR, ZIC1<\/jats:italic> and <jats:italic>SST<\/jats:italic> were evaluated relative to the <jats:italic>ACTB<\/jats:italic> reference gene by multiplex quantitative methylation\u2010specific PCR (qMSP) in clinician\u2010collected cervical samples (n\u00a0=\u00a0715) from hrHPV\u2010positive women (age 29\u201060\u2009years), who were enrolled in the Dutch IMPROVE screening trial (NTR5078). Primary clinical end\u2010point was cervical intraepithelial neoplasia grade 3 (CIN3) or cancer (CIN3+). The single\u2010marker and bi\u2010marker methylation classifiers developed for CIN3 detection in a previous series of hrHPV\u2010positive clinician\u2010collected cervical samples were applied. The diagnostic accuracy was visualised using receiver operating characteristic (ROC) curves and assessed through area under the ROC curve (AUC). The performance of the methylation markers to detect CIN3+ was determined using the predefined threshold calibrated at 70% clinical specificity. Individual methylation makers showed good performance for CIN3+ detection, with highest AUC for <jats:italic>ASCL1<\/jats:italic> (0.844) and <jats:italic>LHX8<\/jats:italic> (0.830). Combined as a bi\u2010marker panel with predefined threshold, <jats:italic>ASCL1\/LHX8<\/jats:italic> yielded a CIN3+ sensitivity of 76.9% (70\/91; 95% CI 68.3\u201085.6%) at a specificity of 74.5% (465\/624; 95% CI 71.1\u201077.9%). In conclusion, our study shows that the individual host\u2010cell DNA methylation classifiers and the bi\u2010marker panel <jats:italic>ASCL1\/LHX8<\/jats:italic> have clinical utility for the detection of CIN3+ in hrHPV\u2010positive women invited for routine screening.<\/jats:p>","DOI":"10.1002\/ijc.33820","type":"journal-article","created":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T10:44:49Z","timestamp":1632480289000},"page":"440-449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Performance of <scp>DNA<\/scp> methylation analysis of <i><scp>ASCL1<\/scp>, <scp>LHX8<\/scp>, <scp>ST6GALNAC5<\/scp>, <scp>GHSR<\/scp>, <scp>ZIC1<\/scp><\/i> and <scp><i>SST<\/i><\/scp> for the triage of <scp>HPV<\/scp>\u2010positive women: Results from a Dutch primary <scp>HPV<\/scp>\u2010based screening cohort"],"prefix":"10.1002","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-0297","authenticated-orcid":false,"given":"Lisanne","family":"Verhoef","sequence":"first","affiliation":[{"name":"Amsterdam UMC Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9610-8064","authenticated-orcid":false,"given":"Maaike C. G.","family":"Bleeker","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8216-7098","authenticated-orcid":false,"given":"Nicole","family":"Polman","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2327-9839","authenticated-orcid":false,"given":"Renske D. M.","family":"Steenbergen","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2758-9463","authenticated-orcid":false,"given":"Chris J. L. M.","family":"Meijer","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5446-2230","authenticated-orcid":false,"given":"Willem J. G.","family":"Melchers","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Medical Microbiology  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4577-8495","authenticated-orcid":false,"given":"Ruud L.","family":"Bekkers","sequence":"additional","affiliation":[{"name":"GROW School for Oncology and Developmental Biology Maastricht University  Maastricht The Netherlands"},{"name":"Department of Obstetrics and Gynaecology Catharina Hospital  Eindhoven The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5516-3005","authenticated-orcid":false,"given":"Anco C.","family":"Molijn","sequence":"additional","affiliation":[{"name":"DDL Diagnostic Laboratory NMDL\u2010LCPL  Rijswijk The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim G.","family":"Quint","sequence":"additional","affiliation":[{"name":"DDL Diagnostic Laboratory NMDL\u2010LCPL  Rijswijk The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4225-4354","authenticated-orcid":false,"given":"Folkert J.","family":"van Kemenade","sequence":"additional","affiliation":[{"name":"Erasmus MC University Medical Center, Pathology  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2094-2380","authenticated-orcid":false,"given":"Johannes","family":"Berkhof","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Vrije Universiteit Amsterdam, Epidemiology and Data Science  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6463-7391","authenticated-orcid":false,"given":"Dani\u00eblle A. M.","family":"Heideman","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2019.09.006"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cyt.12835"},{"key":"e_1_2_10_4_1","first-page":"3225","article-title":"A gene hypermethylation profile of human cancer","volume":"61","author":"Esteller M","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dji041"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3728"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0593-4"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.16395"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2641"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3615"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.2217\/epi-2019-0331"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30763-0"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2003.011841"},{"key":"e_1_2_10_14_1","first-page":"19","article-title":"Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive","volume":"29","author":"Casparie M","year":"2007","journal-title":"Cell Oncol"},{"key":"e_1_2_10_15_1","volume-title":"WHO Classification of Tumours Female Genital Tumours","author":"Editorial Board WCoT","year":"2020"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33566"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.26496"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33320"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0116"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2015.1006506"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy601"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2233"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-267500"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00412"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0037"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.33820","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ijc.33820","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.33820","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T06:52:43Z","timestamp":1737615163000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.33820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,13]]},"references-count":26,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1002\/ijc.33820"],"URL":"https:\/\/doi.org\/10.1002\/ijc.33820","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,13]]},"assertion":[{"value":"2021-05-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}