{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:24:29Z","timestamp":1793053469101,"version":"4.5.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI","doi-asserted-by":"publisher","award":["5U01CA078527"],"award-info":[{"award-number":["5U01CA078527"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The widespread introduction of Pap testing in the 1960s was followed by substantial reductions in the incidence of cervical squamous cell cancer (SCC). However, the incidence of cervical adenocarcinoma (ADC) did not decrease, likely because of low Pap test sensitivity for ADC and adenocarcinoma in situ (AIS). This study assessed a novel human papillomavirus (HPV) and host DNA Methylation Score for AIS and ADC screening.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We measured methylation levels at CpG sites in the L2\/L1 open reading frames of HPV16, HPV18, and HPV45\u2014as well as 2 human loci, DCC and HS3ST2. Specifically, we tested exfoliated cervicovaginal cells from women in the HPV Persistence and Progression (PaP) cohort who were positive for 1 of HPV16, 18, or 45, including: 1) 176 with\u00a0AIS\/ADC, 2) 353 with cervical intraepithelial neoplasia\u20133 (CIN3) or SCC, and 3) controls who either cleared (HPV-Clearers; n\u2009=\u2009579) or had persistent HPV16, 18, or 45 infection (HPV-Persisters; n\u2009=\u2009292). CpG site\u2013specific methylation percentages were measured using our reported next-generation methods. The Methylation Score was the average methylation percentage across all 35 CpG sites tested.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Each individual CpG site had higher methylation percentages in exfoliated cervicovaginal cells collected from patients with AIS\/ADC, and as well as those with CIN3\/SCC, relative to either control group (weakest P \u2009=\u2009.004). The Methylation Score for AIS\/ADC had a sensitivity\u2009of\u200974% and specificity\u2009of\u200989%. The multivariate odds ratio (OR) between the Methylation Score (4th vs 1st quartile) for AIS\/ADC was ORq4-q1\u2009=\u200949.01 (PBenjamini-Hochberg\u2009=\u20094.64E-12), using HPV-Clearers as controls. CIN3\/SCC had similar, albeit weaker, associations with the Methylation Score.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>HPV16\/18\/45-infected women with Methylation Scores in the highest quartile had very high odds of AIS\/ADC, suggesting they may warrant careful histologic evaluation of the cervical transition zone (eg, conization or loop electrosurgical excision procedure [LEEP]).<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jnci\/djad134","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T23:50:21Z","timestamp":1689810621000},"page":"1535-1543","source":"Crossref","is-referenced-by-count":8,"title":["A novel human papillomavirus and host DNA methylation score and detection of cervical adenocarcinoma"],"prefix":"10.1093","volume":"115","author":[{"given":"Ana","family":"Gradissimo","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Albert Einstein College of Medicine , Bronx, NY, USA"},{"name":"Department of Immunology, Memorial Sloan Kettering Cancer Center , Manhattan, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0435-7376","authenticated-orcid":false,"given":"Megan A","family":"Clarke","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaonan","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Epidemiology & Population Health, Albert Einstein College of Medicine , Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip E","family":"Castle","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD, USA"},{"name":"Department of Epidemiology & Population Health, Albert Einstein College of Medicine , Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina R","family":"Raine-Bennett","sequence":"additional","affiliation":[{"name":"Kaiser Permanente Division of Research , Oakland, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4625-2508","authenticated-orcid":false,"given":"Mark","family":"Schiffman","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1251-0836","authenticated-orcid":false,"given":"Nicolas","family":"Wentzensen","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6397-7466","authenticated-orcid":false,"given":"Howard D","family":"Strickler","sequence":"additional","affiliation":[{"name":"Department of Epidemiology & Population Health, Albert Einstein College of Medicine , Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D","family":"Burk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Albert Einstein College of Medicine , Bronx, NY, USA"},{"name":"Department of Epidemiology & Population Health, Albert Einstein College of Medicine , Bronx, NY, USA"},{"name":"Departments of Microbiology & Immunology, Gynecology & Women\u2019s Health, Albert Einstein College of Medicine , Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"issue":"3","key":"2023120620223120700_djad134-B1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"2023120620223120700_djad134-B2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/his.13995","article-title":"Cervical adenocarcinoma: integration of HPV status, pattern of invasion, morphology and molecular markers into 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