{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:01:49Z","timestamp":1790010109837,"version":"4.0.1"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T00:00:00Z","timestamp":1734998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"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"}]},{"name":"Amsterdam Academic Medical Centres"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>High-resolution anoscopy (HRA) to prevent anal cancer is complex and screening capacity is limited. Previously, DNA methylation analysis of anal high-grade squamous intraepithelial lesion (HSIL) biopsies was shown to distinguish between HSIL with an increased and a low cancer risk, supporting personalized treatment. Here, methylation analysis on anal swabs was assessed to detect underlying HSIL with an increased cancer risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A cross-sectional series of paired anal swabs and biopsies of 215 persons with human immunodeficiency virus and swabs of 19 cancer patients were tested for 6 methylation markers. Data were analyzed by logistic regression analysis. The primary endpoint was methylation-positive biopsy HSIL (M+ HSIL), indicating increased cancer risk. Test performance of methylation markers, human papillomavirus (HPV), and\/or cytology, and cancer detection and HRA referral, were calculated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Anal cancer swabs showed highest methylation. ZNF582 and panels ASCL1\/ZNF582 and LHX8\/ZNF582 yielded an area under the curve of 0.68\u20130.70 to detect underlying M+ HSIL. Methylation at 80% sensitivity corresponded to 43% fewer patients requiring HRA, without missing any cancers and detecting 79% of HPV-16\u2013positive HSIL-AIN3. Methylation\/HPV and cytology\/HPV co-testing performed similarly.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Methylation levels in anal swabs reflect underlying anal disease. Methylation analysis could reduce HRA referrals substantially, while maintaining a high sensitivity for M+ HSIL and detecting all cancers. These results encourage screening on anal swabs to preselect patients needing HRA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiae627","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T07:38:02Z","timestamp":1734680282000},"page":"1040-1049","source":"Crossref","is-referenced-by-count":11,"title":["DNA Methylation Analysis on Anal Swabs for Anal Cancer Screening in People Living With Human Immunodeficiency Virus"],"prefix":"10.1093","volume":"232","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0546-7956","authenticated-orcid":false,"given":"Fernando","family":"Dias Gon\u00e7alves Lima","sequence":"first","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam"},{"name":"Department of Dermatology, Amsterdam UMC, location University of Amsterdam"},{"name":"Amsterdam Institute for Infection and Immunity"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9597-1728","authenticated-orcid":false,"given":"Kirsten","family":"Rozemeijer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1325-1901","authenticated-orcid":false,"given":"Ramon P","family":"van der Zee","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam"},{"name":"Amsterdam Institute for Infection and Immunity"},{"name":"Division of Infectious Diseases, Department of Internal Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5548-4557","authenticated-orcid":false,"given":"St\u00e8fanie","family":"Dick","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam"},{"name":"Department of Radiation Oncology, Amsterdam UMC, location University of Amsterdam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7490-0074","authenticated-orcid":false,"given":"Timo J","family":"ter Braak","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-5054","authenticated-orcid":false,"given":"Debby E","family":"Geijsen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Amsterdam UMC, location University of Amsterdam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4222-6595","authenticated-orcid":false,"given":"Philip","family":"Meijnen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Amsterdam UMC, location Vrije Universiteit Amsterdam"}],"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":"Department of Epidemiology and Data Science, Amsterdam UMC, location Vrije Universiteit Amsterdam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7907-7390","authenticated-orcid":false,"given":"Carel J M","family":"van Noesel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location University of Amsterdam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9784-547X","authenticated-orcid":false,"given":"Henry J C","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Amsterdam UMC, location University of Amsterdam"},{"name":"Amsterdam Institute for Infection and Immunity"},{"name":"Department of Infectious Diseases, Sexually Transmitted Infection Outpatient Clinic, Public Health Service of Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5415-8933","authenticated-orcid":false,"given":"Jan M","family":"Prins","sequence":"additional","affiliation":[{"name":"Amsterdam Institute for Infection and Immunity"},{"name":"Division of Infectious Diseases, Department of Internal Medicine"}],"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 UMC, location Vrije Universiteit Amsterdam"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,24]]},"reference":[{"key":"2025112208022472800_jiae627-B1","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1056\/NEJMoa2201048","article-title":"Treatment of anal high-grade squamous intraepithelial lesions to prevent anal cancer","volume":"386","author":"Palefsky","year":"2022","journal-title":"N Engl J Med"},{"key":"2025112208022472800_jiae627-B2","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1002\/ijc.34850","article-title":"International Anal Neoplasia Society\u2019s consensus guidelines for anal cancer screening","volume":"154","author":"Stier","year":"2024","journal-title":"Int J Cancer"},{"key":"2025112208022472800_jiae627-B3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1002\/ijc.33185","article-title":"A meta-analysis of anal cancer incidence by risk group: toward a unified anal cancer risk scale","volume":"148","author":"Clifford","year":"2021","journal-title":"Int J Cancer"},{"key":"2025112208022472800_jiae627-B4","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1097\/QAD.0000000000000227","article-title":"Screening for anal cancer precursors: what is the learning curve for high-resolution anoscopy?","volume":"28","author":"Richel","year":"2014","journal-title":"AIDS"},{"key":"2025112208022472800_jiae627-B5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/DCR.0000000000000511","article-title":"Health-related quality of life and sexual functioning of HIV-positive men who have sex with men who are treated for anal intraepithelial neoplasia","volume":"59","author":"Siegenbeek van Heukelom","year":"2016","journal-title":"Dis Colon Rectum"},{"key":"2025112208022472800_jiae627-B6","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 Oncol"},{"key":"2025112208022472800_jiae627-B7","doi-asserted-by":"crossref","first-page":"e97","DOI":"10.1016\/S2352-3018(22)00368-X","article-title":"Effect of the introduction of screening for cancer precursor lesions on anal cancer incidence over time in people living with HIV: a nationwide cohort study","volume":"10","author":"van der Zee","year":"2023","journal-title":"Lancet HIV"},{"key":"2025112208022472800_jiae627-B8","doi-asserted-by":"crossref","first-page":"ofz191","DOI":"10.1093\/ofid\/ofz191","article-title":"The accuracy of anal swab-based tests to detect high-grade anal intraepithelial neoplasia in HIV-infected patients: a systematic review and meta-analysis","volume":"6","author":"Dias Gon\u00e7alves Lima","year":"2019","journal-title":"Open Forum Infect Dis"},{"key":"2025112208022472800_jiae627-B9","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1002\/ijc.34199","article-title":"A systematic review and meta-analysis of cytology and HPV-related biomarkers for anal cancer screening among different risk groups","volume":"151","author":"Clarke","year":"2022","journal-title":"Int J Cancer"},{"key":"2025112208022472800_jiae627-B10","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1093\/cid\/ciaa399","article-title":"Molecular risk stratification for anal cancer prevention","volume":"72","author":"Clifford","year":"2021","journal-title":"Clin Infect Dis"},{"key":"2025112208022472800_jiae627-B11","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/nrc3728","article-title":"Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions","volume":"14","author":"Steenbergen","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"2025112208022472800_jiae627-B12","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1093\/cid\/ciaa397","article-title":"Cancer risk stratification of anal intraepithelial neoplasia in human immunodeficiency virus\u2013positive men by validated methylation markers associated with progression to cancer","volume":"72","author":"van der Zee","year":"2021","journal-title":"Clin Infect Dis"},{"key":"2025112208022472800_jiae627-B13","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1093\/cid\/ciy601","article-title":"Host cell deoxyribonucleic acid methylation markers for the detection of high-grade anal intraepithelial neoplasia and anal cancer","volume":"68","author":"van der Zee","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2025112208022472800_jiae627-B14","doi-asserted-by":"crossref","first-page":"200275","DOI":"10.1016\/j.tvr.2023.200275","article-title":"Analytical validation and diagnostic performance of the ASCL1\/ZNF582 methylation test for detection of high-grade anal intraepithelial neoplasia and anal cancer","volume":"17","author":"Rozemeijer","year":"2024","journal-title":"Tumour Virus Res"},{"key":"2025112208022472800_jiae627-B15","doi-asserted-by":"crossref","first-page":"e060301","DOI":"10.1136\/bmjopen-2021-060301","article-title":"DNA methylation analysis to predict regression of high-grade anal intraepithelial neoplasia in HIV+ men (MARINE): a cohort study protocol","volume":"12","author":"Dias Gon\u00e7alves Lima","year":"2022","journal-title":"BMJ Open"},{"key":"2025112208022472800_jiae627-B16","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/j.ijsu.2014.07.013","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies","volume":"12","author":"von Elm","year":"2014","journal-title":"Int J Surg"},{"key":"2025112208022472800_jiae627-B17","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/LGT.0000000000000256","article-title":"2016 IANS international guidelines for practice standards in the detection of anal cancer precursors","volume":"20","author":"Hillman","year":"2016","journal-title":"J Low Genit Tract Dis"},{"key":"2025112208022472800_jiae627-B18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1097\/LGT.0000000000000458","article-title":"International Anal Neoplasia Society guidelines for the practice of digital anal rectal examination","volume":"23","author":"Hillman","year":"2019","journal-title":"J Low Genit Tract Dis"},{"key":"2025112208022472800_jiae627-B19","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1001\/jama.287.16.2114","article-title":"The 2001 Bethesda system: terminology for reporting results of cervical cytology","volume":"287","author":"Solomon","year":"2002","journal-title":"JAMA"},{"key":"2025112208022472800_jiae627-B20","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/cncy.21521","article-title":"The pap test and Bethesda 2014","volume":"123","author":"Nayar","year":"2015","journal-title":"Cancer Cytopathol"},{"key":"2025112208022472800_jiae627-B21","doi-asserted-by":"crossref","first-page":"3024","DOI":"10.1002\/1878-0261.12926","article-title":"DNA methylation markers have universal prognostic value for anal cancer risk in HIV-negative and HIV-positive individuals","volume":"15","author":"van der Zee","year":"2021","journal-title":"Mol Oncol"},{"key":"2025112208022472800_jiae627-B22","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1186\/1471-2407-12-551","article-title":"Development of a multiplex methylation-specific PCR as candidate triage test for women with an HPV-positive cervical scrape","volume":"12","author":"Snellenberg","year":"2012","journal-title":"BMC Cancer"},{"key":"2025112208022472800_jiae627-B23","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat Protoc"},{"key":"2025112208022472800_jiae627-B24","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.5858\/arpa.LGT200570","article-title":"The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology","volume":"136","author":"Darragh","year":"2012","journal-title":"Arch Pathol Lab Med"},{"key":"2025112208022472800_jiae627-B25","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/ijc.29706","article-title":"CADM1 and MAL methylation status in cervical scrapes is representative of the most severe underlying lesion in women with multiple cervical biopsies","volume":"138","author":"van Baars","year":"2016","journal-title":"Int J Cancer"},{"key":"2025112208022472800_jiae627-B26","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.1038\/s41598-022-07258-5","article-title":"Gene methylation of CADM1 and MAL identified as a biomarker of high grade anal intraepithelial neoplasia","volume":"12","author":"Phillips","year":"2022","journal-title":"Sci Rep"},{"key":"2025112208022472800_jiae627-B27","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1093\/cid\/ciz336","article-title":"Pilot study of markers for high-grade anal dysplasia in a southern cohort from the Women's Interagency Human Immunodeficiency Virus Study","volume":"70","author":"Lahiri","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2025112208022472800_jiae627-B28","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1093\/cid\/ciac211","article-title":"Automated evaluation of p16\/Ki-67 dual-stain cytology as a biomarker for detection of anal precancer in men who have sex with men and are living with human immunodeficiency virus","volume":"75","author":"Cohen","year":"2022","journal-title":"Clin Infect Dis"},{"key":"2025112208022472800_jiae627-B29","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1002\/ijc.32614","article-title":"FAM19A4\/miR124-2 methylation in invasive cervical cancer: a retrospective cross-sectional worldwide study","volume":"147","author":"Vink","year":"2020","journal-title":"Int J Cancer"},{"key":"2025112208022472800_jiae627-B30","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1002\/ijc.31539","article-title":"Cervical cancer risk in HPV-positive women after a negative FAM19A4\/mir124-2 methylation test: a post hoc analysis in the POBASCAM trial with 14 year follow-up","volume":"143","author":"De Strooper","year":"2018","journal-title":"Int J Cancer"},{"key":"2025112208022472800_jiae627-B31","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/ijc.33815","article-title":"Clinical performance of methylation as a biomarker for cervical carcinoma in situ and cancer diagnosis: a worldwide study","volume":"150","author":"Banila","year":"2022","journal-title":"Int J Cancer"},{"key":"2025112208022472800_jiae627-B32","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1158\/1055-9965.EPI-15-1106","article-title":"A composite cytology-histology endpoint allows a more accurate estimate of anal high-grade squamous intraepithelial lesion prevalence","volume":"25","author":"Machalek","year":"2016","journal-title":"Cancer Epidemiol Biomarkers Prev"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiae627\/61272321\/jiae627.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/232\/5\/1040\/61272321\/jiae627.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/232\/5\/1040\/61272321\/jiae627.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T13:02:35Z","timestamp":1763816555000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/232\/5\/1040\/7932177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,24]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,12,24]]},"published-print":{"date-parts":[[2025,11,14]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiae627","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,11,15]]},"published":{"date-parts":[[2024,12,24]]}}}