{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:44:40Z","timestamp":1783075480620,"version":"3.54.6"},"reference-count":35,"publisher":"BMJ","issue":"4","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Clin Pathol"],"accepted":{"date-parts":[[2017,8,16]]},"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To assess differences in methylation profiles, and thus pathogenesis, between Epstein-Barr virus (EBV)-positive and negative nasopharyngeal carcinomas (NPCs). Also, promoter hypermethylation is a common phenomenon in early carcinogenesis to inactivate tumour suppressor genes. Since epigenetic changes are reversible, the therapeutic application of methylation inhibitors could provide treatment options.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated promoter hypermethylation profiles of 22 common tumour suppressor genes in 108 NPCs using methylation-specific multiplex ligation-dependent probe amplification. Correlation between methylation, clinicopathological features (including EBV) and survival was examined. Cluster analysis was also performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hypermethylation of RASSF1A and ESR1 was significantly more frequent in EBV-positive NPC, while hypermethylation of DAPK1 was more frequent in EBV-negative NPC. In logistic regression, age, with EBV-positive NPC occurring at earlier age, and RASSF1, with RASSF1 hypermethylation being more frequent in EBV-positive NPC, remained significant. In EBV-positive NPC, hypermethylation of RASSF1A predicted worse overall survival (OS) (HR 3.058,95% CI 1.027 to 9.107). In EBV-negative NPC, hypermethylated adenomatous polyposis coli (APC) was a predictor of poor disease-free survival (DFS) (HR 6.868, 95%\u2009CI 2.142 to 22.022).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>There are important epigenetic differences between EBV-negative and EBV-positive NPCs, with EBV-negative NPC having a more similar hypermethylation profile to other head and neck squamous cell carcinomas than EBV-positive NPC. Hypermethylation of RASSF1A might contribute to worse OS in EBV-positive NPC, and may be an important event in the pathogenesis of EBV-infected NPC. Hypermethylation of APC might contribute to worse DFS in EBV-negative NPC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jclinpath-2017-204661","type":"journal-article","created":{"date-parts":[[2017,9,11]],"date-time":"2017-09-11T20:50:22Z","timestamp":1505163022000},"page":"351-359","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification"],"prefix":"10.1136","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2202-7066","authenticated-orcid":false,"given":"Marc L","family":"Ooft","sequence":"first","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolique","family":"van Ipenburg","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"van Loo","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Moelans","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibel","family":"Braunius","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remco","family":"de Bree","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"van Diest","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senada","family":"Koljenovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Baatenburg de Jong","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Hardillo","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan M","family":"Willems","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2017,9,11]]},"reference":[{"key":"2025120520235932000_71.4.351.1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-06-0353"},{"key":"2025120520235932000_71.4.351.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2014.02.006"},{"key":"2025120520235932000_71.4.351.3","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25696"},{"key":"2025120520235932000_71.4.351.4","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19960115)77:2<231::AID-CNCR2>3.0.CO;2-P"},{"key":"2025120520235932000_71.4.351.5","doi-asserted-by":"publisher","DOI":"10.1177\/000348949710600416"},{"key":"2025120520235932000_71.4.351.6","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/978-3-319-24738-0_3","article-title":"Epigenetic alterations in epstein-barr virus-associated diseases","volume":"879","author":"Niller","year":"2016","journal-title":"Adv Exp Med Biol"},{"key":"2025120520235932000_71.4.351.7","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.325.7365.648"},{"key":"2025120520235932000_71.4.351.8","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23716"},{"key":"2025120520235932000_71.4.351.9","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1002\/cam4.499","article-title":"Clinical relevance of copy number profiling in oral and oropharyngeal squamous cell carcinoma","volume":"4","author":"van Kempen","year":"2015","journal-title":"Cancer Med"},{"key":"2025120520235932000_71.4.351.10","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.4161\/epi.29785","article-title":"Promoter hypermethylation using 24-gene array in early head and neck cancer: better outcome in oral than in oropharyngeal cancer","volume":"9","author":"Noorlag","year":"2014","journal-title":"Epigenetics"},{"key":"2025120520235932000_71.4.351.11","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2559.2002.14892.x"},{"key":"2025120520235932000_71.4.351.12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gni127"},{"key":"2025120520235932000_71.4.351.13","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s13148-011-0045-3","article-title":"Role of DNA methylation in head and neck cancer","volume":"2","author":"Demokan","year":"2011","journal-title":"Clin Epigenetics"},{"key":"2025120520235932000_71.4.351.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2005.06.014"},{"key":"2025120520235932000_71.4.351.15","doi-asserted-by":"publisher","DOI":"10.1002\/path.2930"},{"key":"2025120520235932000_71.4.351.16","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2006.114876"},{"key":"2025120520235932000_71.4.351.17","doi-asserted-by":"publisher","DOI":"10.1186\/bcr3220"},{"key":"2025120520235932000_71.4.351.18","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdn409"},{"key":"2025120520235932000_71.4.351.19","doi-asserted-by":"publisher","DOI":"10.21037\/cco.2016.03.06"},{"key":"2025120520235932000_71.4.351.20","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.cell.2015.08.005","article-title":"DNA Methylation inhibitors in cancer therapy: the immunity dimension","volume":"162","author":"Licht","year":"2015","journal-title":"Cell"},{"key":"2025120520235932000_71.4.351.21","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-380866-0.60012-5"},{"key":"2025120520235932000_71.4.351.22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2119\/molmed.2010.00239","article-title":"Altered methylation at microRNA-associated CpG islands in hereditary and sporadic carcinomas: a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)-based approach","volume":"17","author":"Pavicic","year":"2011","journal-title":"Mol Med"},{"key":"2025120520235932000_71.4.351.23","doi-asserted-by":"crossref","first-page":"797","DOI":"10.4103\/0970-9290.152208","article-title":"Promoter hypermethylation patterns of P16, DAPK and MGMT in oral squamous cell carcinoma: a systematic review and meta-analysis","volume":"25","author":"Don","year":"2014","journal-title":"Indian J Dent Res"},{"key":"2025120520235932000_71.4.351.24","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.313"},{"key":"2025120520235932000_71.4.351.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2012.01.018"},{"key":"2025120520235932000_71.4.351.26","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63511-0"},{"key":"2025120520235932000_71.4.351.27","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.92"},{"key":"2025120520235932000_71.4.351.28","doi-asserted-by":"publisher","DOI":"10.1593\/neo.05217"},{"key":"2025120520235932000_71.4.351.29","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-10-48"},{"key":"2025120520235932000_71.4.351.30","doi-asserted-by":"publisher","DOI":"10.1155\/2007\/291538"},{"key":"2025120520235932000_71.4.351.31","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/cncr.24113","article-title":"Microtubule-damaging agents enhance RASSF1A-induced cell death in lung cancer cell lines","volume":"115","author":"Whang","year":"2009","journal-title":"Cancer"},{"key":"2025120520235932000_71.4.351.32","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s00280-012-2020-x","article-title":"Triplet combination with paclitaxel, cisplatin and 5-FU is effective in metastatic and\/or recurrent nasopharyngeal carcinoma","volume":"71","author":"Chen","year":"2013","journal-title":"Cancer Chemother Pharmacol"},{"key":"2025120520235932000_71.4.351.33","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1111\/odi.12357","article-title":"Molecular characterization of oral squamous cell carcinoma using targeted next-generation sequencing","volume":"21","author":"Tk","year":"2015","journal-title":"Oral diseases"},{"key":"2025120520235932000_71.4.351.34","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1750-9378-8-30","article-title":"Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population","volume":"8","author":"Robinson","year":"2013","journal-title":"Infect Agent Cancer"},{"key":"2025120520235932000_71.4.351.35","doi-asserted-by":"publisher","DOI":"10.1097\/PDM.0b013e3182595516"}],"container-title":["Journal of Clinical Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jclinpath-2017-204661","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T04:24:11Z","timestamp":1764995051000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcp.bmj.com\/lookup\/doi\/10.1136\/jclinpath-2017-204661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,11]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,3,20]]},"published-print":{"date-parts":[[2018,4]]}},"alternative-id":["10.1136\/jclinpath-2017-204661"],"URL":"https:\/\/doi.org\/10.1136\/jclinpath-2017-204661","relation":{},"ISSN":["0021-9746","1472-4146"],"issn-type":[{"value":"0021-9746","type":"print"},{"value":"1472-4146","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,11]]}}}