{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T23:08:07Z","timestamp":1791932887720,"version":"4.3.4"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"European Union Horizon"},{"name":"2020"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>High-grade squamous intraepithelial lesions (HSIL) or cervical intraepithelial neoplasia (CIN) grade 2\/3 lesions in human papillomavirus (HPV)\u2013positive women &amp;lt;30 years of age have high spontaneous regression rates. To reduce overtreatment, biomarkers are needed to delineate advanced CIN lesions that require treatment. We analyzed the FAM19A4\/miR124-2 methylation test and HPV16\/18 genotyping in HPV-positive women aged &amp;lt;30 years, aiming to identify CIN2\/3 lesions in need of treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A European multicenter retrospective study was designed evaluating the FAM19A4\/miR124-2 methylation test and HPV16\/18 genotyping in cervical scrapes of 1061 HPV-positive women aged 15\u201329 years (690 \u2264CIN1, 166 CIN2, and 205 CIN3+). A subset of 62 CIN2 and 103 CIN3 were immunohistochemically characterized by HPV E4 expression, a marker for a productive HPV infection, and p16ink4a and Ki-67, markers indicative for a transforming infection. CIN2\/3 lesions with low HPV E4 expression and high p16ink4a\/Ki-67 expression were considered as nonproductive, transforming CIN, compatible with advanced CIN2\/3 lesions in need of treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FAM19A4\/miR124-2 methylation positivity increased significantly with CIN grade and age groups (&amp;lt;25, 25\u201329, and \u226530 years), while HPV16\/18 positivity was comparable across age groups. FAM19A4\/miR124-2 methylation positivity was HPV type independent. Methylation-positive CIN2\/3 lesions had higher p16ink4a\/Ki-67-immunoscores (P = .003) and expressed less HPV E4 (P = .033) compared with methylation-negative CIN2\/3 lesions. These differences in HPV E4 and p16ink4a\/Ki-67 expression were not found between HPV16\/18\u2013positive and non-16\/18 HPV\u2013positive lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Compared with HPV16\/18 genotyping, the FAM19A4\/miR124-2 methylation test detects nonproductive, transforming CIN2\/3 lesions with high specificity in women aged &amp;lt;30 years, providing clinicians supportive information about the need for treatment of CIN2\/3 in young HPV-positive women.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciac433","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T02:34:11Z","timestamp":1654828451000},"page":"e827-e834","source":"Crossref","is-referenced-by-count":29,"title":["<i>FAM19A4\/miR124-2<\/i>\n                    Methylation Testing and Human Papillomavirus (HPV) 16\/18 Genotyping in HPV-Positive Women Under the Age of 30 Years"],"prefix":"10.1093","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-9167","authenticated-orcid":false,"given":"Frederique J","family":"Vink","sequence":"first","affiliation":[{"name":"Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Pathology , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, 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 University Medical Center, Vrije Universiteit Amsterdam, Pathology , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4282-4417","authenticated-orcid":false,"given":"Albertus T","family":"Hesselink","sequence":"additional","affiliation":[{"name":"Self-screen B.V. , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-2688","authenticated-orcid":false,"given":"Arno N","family":"Floore","sequence":"additional","affiliation":[{"name":"Self-screen B.V. , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9448-1826","authenticated-orcid":false,"given":"Birgit I","family":"Lissenberg-Witte","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Epidemiology and Data Science , Amsterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4853-6747","authenticated-orcid":false,"given":"Jesper H","family":"Bonde","sequence":"additional","affiliation":[{"name":"Molecular Pathology Laboratory, Department of Pathology, Copenhagen University Hospital, Hvidovre Hospital , Hvidovre , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helle","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Molecular Pathology Laboratory, Department of Pathology, Copenhagen University Hospital, Hvidovre Hospital , Hvidovre , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2604-3928","authenticated-orcid":false,"given":"Kate","family":"Cuschieri","sequence":"additional","affiliation":[{"name":"Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh, NHS Lothian , Edinburgh, Scotland"},{"name":"Centre for Reproductive Health, University of Edinburgh , Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-0668","authenticated-orcid":false,"given":"Ramya","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh, NHS Lothian , Edinburgh, Scotland"},{"name":"Centre for Reproductive Health, University of Edinburgh , Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-7564","authenticated-orcid":false,"given":"Mario","family":"Poljak","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3061-5319","authenticated-orcid":false,"given":"Anja","family":"O\u0161trbenk Valen\u010dak","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9829-3531","authenticated-orcid":false,"given":"Peter","family":"Hillemanns","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Hannover Medical School , Hannover , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim G V","family":"Quint","sequence":"additional","affiliation":[{"name":"DDL Diagnostic Laboratory , Rijswijk , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2178-2403","authenticated-orcid":false,"given":"Marta","family":"del Pino","sequence":"additional","affiliation":[{"name":"Institut Clinic of Gynecology, Obstetrics and Neonatology, Gynecology Oncology Unit, Hospital Cl\u00ednic-Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer, Faculty of Medicine, University of Barcelona , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7284-3918","authenticated-orcid":false,"given":"Gemma G","family":"Kenter","sequence":"additional","affiliation":[{"name":"Center for Gynecologic Oncology Amsterdam, Amsterdam University Medical Center and Netherlands Cancer Institute , 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 University Medical Center, Vrije Universiteit Amsterdam, Pathology , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam, 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 University Medical Center, Vrije Universiteit Amsterdam, Pathology , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, 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 University Medical Center, Vrije Universiteit Amsterdam, Pathology , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam, Amsterdam , The 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