{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:16:20Z","timestamp":1778127380833,"version":"3.51.4"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Oral Pathology Medicine"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Methylation of tumor\u2010suppressor gene promoters, particularly\n                      <jats:italic>p16<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>INK4A<\/jats:italic>\n                      <\/jats:sup>\n                      , is implicated in oral carcinogenesis. Although associations with oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD) have been reported, no systematic review has examined these conditions while assessing evidence certainty. This review evaluated whether\n                      <jats:italic>p16<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>INK4A<\/jats:italic>\n                      <\/jats:sup>\n                      promoter methylation is associated with OSCC and OPMD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      PubMed, Embase, Web of Science, Scopus, Livivo, and Google Scholar were searched. Studies were selected by title\/abstract and then full\u2010text review. Eligible studies investigated\n                      <jats:italic>p16<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>INK4A<\/jats:italic>\n                      <\/jats:sup>\n                      methylation in OSCC or OPMD with comparator groups. Data were meta\u2010analyzed using random\u2010effects models to obtain pooled odds ratios (OR). Heterogeneity, publication bias, sensitivity analyses, and prediction intervals were assessed. Evidence certainty was rated using GRADE.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Twenty\u2010four studies were included, comprising 1330 OSCC patients, 606 OPMD patients, and 681 healthy controls. Meta\u2010analyses demonstrated a strong association between\n                      <jats:italic>p16<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>INK4A<\/jats:italic>\n                      <\/jats:sup>\n                      methylation and OSCC when compared with healthy controls (OR\u2009=\u200911.59; 95% CI\u2009=\u20096.01\u201322.37;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), with surgical margins (OR\u2009=\u20093.24; 95% CI\u2009=\u20091.86\u20135.65;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and with OPMD (OR\u2009=\u20093.72; 95% CI\u2009=\u20092.47\u20135.59;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). OPMD also showed increased methylation versus healthy controls (OR\u2009=\u200924.8; 95% CI\u2009=\u20097.4\u201383.14;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>p16<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>INK4A<\/jats:italic>\n                      <\/jats:sup>\n                      methylation is strongly associated with OSCC and OPMD; however, due to heterogeneity and low certainty of evidence, these findings should be interpreted cautiously. Further standardized, well\u2010designed studies are needed to clarify the role of\n                      <jats:italic>p16<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>INK4A<\/jats:italic>\n                      <\/jats:sup>\n                      methylation in oral carcinogenesis.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:bold>Trial Registration:<\/jats:bold>\n                      International Prospective Register of Systematic Reviews (PROSPERO): CRD42023410477\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jop.70119","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T07:26:11Z","timestamp":1769844371000},"page":"591-600","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of\n                    <scp>\n                      <i>p16<\/i>\n                      <sup>\n                        <i>INK4A<\/i>\n                      <\/sup>\n                    <\/scp>\n                    Methylation With Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review and Meta\u2010Analysis"],"prefix":"10.1111","volume":"55","author":[{"given":"Rairam Fernandes","family":"de Aguiar","sequence":"first","affiliation":[{"name":"Postgraduate Program in Dentistry, Faculty of Pharmacy, Dentistry and Nursing Federal University of Cear\u00e1  Fortaleza Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis Francisco Gon\u00e7alves","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Department of Pathology and Legal Medicine Federal University of Cear\u00e1  Fortaleza Cear\u00e1 Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas Moreira","family":"de Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Department of Clinical Dentistry, Faculty of Pharmacy, Dentistry and Nursing Federal University of Cear\u00e1  Fortaleza Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6678-9513","authenticated-orcid":false,"given":"Khalil Fernandes","family":"Viana","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Dentistry, Faculty of Pharmacy, Dentistry and Nursing Federal University of Cear\u00e1  Fortaleza Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas Matheus Lima","family":"Farias","sequence":"additional","affiliation":[{"name":"Department of Clinical Dentistry, Faculty of Pharmacy, Dentistry and Nursing Federal University of Cear\u00e1  Fortaleza Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5654-3766","authenticated-orcid":false,"given":"Joyce Magalh\u00e3es","family":"de Barros","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Dentistry, 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