{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:24:21Z","timestamp":1790429061716,"version":"4.1.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T00:00:00Z","timestamp":1586304000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Aidsfonds","award":["P-26606"],"award-info":[{"award-number":["P-26606"]}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["2016-10781"],"award-info":[{"award-number":["2016-10781"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>High-grade anal intraepithelial neoplasia (HGAIN; AIN2\u20133) is highly prevalent in HIV+\u2005men, but only a minority of these lesions progress towards cancer. Currently, cancer progression risk cannot be established; therefore, no consensus exists on whether HGAIN should be treated. This study aimed to validate previously identified host cell DNA methylation markers for detection and cancer risk stratification of HGAIN.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A large independent cross-sectional series of 345 anal cancer, AIN3, AIN2, AIN1, and normal control biopsies of HIV+\u2005men was tested for DNA methylation of 6 genes using quantitative methylation-specific PCR. We determined accuracy for detection of AIN3 and cancer (AIN3+) by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Methylation levels were assessed in a series of 10 anal cancer cases with preceding HGAIN at similar anatomic locations, and compared with the cross-sectional series.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Methylation levels of all genes increased with increasing severity of disease (P\u2005&amp;lt;\u2005.05). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. ZNF582 showed highest accuracy (AUC\u2005=\u20050.88) for AIN3+\u2005detection, slightly improved by addition of ASCL1 and SST (AUC\u2005=\u20050.89), forming a marker panel. In the longitudinal series, HGAIN preceding cancer displayed high methylation levels similar to cancers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We validated the accuracy of 5 methylation markers for the detection of anal (pre-) cancer. High methylation levels in HGAIN were associated with progression to cancer. These markers provide a promising tool to identify HGAIN in need of treatment, preventing overtreatment of HGAIN with a low cancer progression risk.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciaa397","type":"journal-article","created":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T22:00:11Z","timestamp":1586296811000},"page":"2154-2163","source":"Crossref","is-referenced-by-count":48,"title":["Cancer Risk Stratification of Anal Intraepithelial Neoplasia in Human Immunodeficiency Virus\u2013Positive Men by Validated Methylation Markers Associated With Progression to Cancer"],"prefix":"10.1093","volume":"72","author":[{"given":"Ramon P","family":"van der Zee","sequence":"first","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands"},{"name":"Department of Internal Medicine, Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Institute for Infection and Immunity (AI&II), Amsterdam, The Netherlands"},{"name":"Department of Dermatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Richel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carel J M","family":"van Noesel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliana","family":"Cioc\u0103nea-Teodorescu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annina P","family":"van Splunter","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo J","family":"ter Braak","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayura","family":"Nathan","sequence":"additional","affiliation":[{"name":"Homerton Anal Neoplasia Service, Homerton University Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamzin","family":"Cuming","sequence":"additional","affiliation":[{"name":"Homerton Anal Neoplasia Service, Homerton University Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sheaff","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology, Barts Health National Health Service (NHS) Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kreuter","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venerology, and Allergology, Helios St Elisabeth Hospital Oberhausen, University Witten\/Herdecke, Oberhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J L M","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands"}],"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"}]},{"given":"Henry J C","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Sexually Transmitted Infections Outpatient Clinic, Department of Infectious Diseases, Public Health Service of Amsterdam (GGD Amsterdam), Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan M","family":"Prins","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Institute for Infection and Immunity (AI&II), 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":"Department of Pathology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,8]]},"reference":[{"key":"2021061514012758100_CIT0001","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S1470-2045(12)70080-3","article-title":"Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis","volume":"13","author":"Machalek","year":"2012","journal-title":"Lancet 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