{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:50:35Z","timestamp":1761094235068,"version":"build-2065373602"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,12,6]],"date-time":"2006-12-06T00:00:00Z","timestamp":1165363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2007,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We investigated whether there is a relationship between loss of p16<jats:sup>INK4a<\/jats:sup> protein expression and p53 alterations in head and neck squamous cell carcinomas (HNSCCs). For this purpose, immunohistochemistry was performed on tissue microarrays of 664 tumours; this represents the largest HNSCC cohort studied for molecular biomarkers. Loss of p16<jats:sup>INK4a<\/jats:sup> protein expression was associated with aberrant p53 expression (negative or overexpressed) in the total cohort, and with <jats:italic>TP53<\/jats:italic> mutations in 200 tumours analysed (<jats:italic>p<\/jats:italic> &lt; 0.0001 each). Both loss of p16<jats:sup>INK4a<\/jats:sup> expression and p53 alterations differed significantly across both tumour sites and stages, being more prevalent in the hypopharynx than in the other tumour sites and in advanced tumour stages. As a possible link between p53 status and p16<jats:sup>INK4a<\/jats:sup> loss, we found that increased DNA methyltransferase 1 protein levels occurred preferentially in tumours with aberrant p53 (<jats:italic>p<\/jats:italic> = 0.001) and negative p16<jats:sup>INK4a<\/jats:sup> expression (<jats:italic>p<\/jats:italic> = 0.0004). In the total cohort, there was a borderline significant difference in patient survival across three p16<jats:sup>INK4a<\/jats:sup> expression levels (negative, positive, high), with loss of p16<jats:sup>INK4a<\/jats:sup> expression showing shortest survival. It is suggested that loss of p16<jats:sup>INK4a<\/jats:sup> expression and p53 alterations should be viewed as related events involved in the early carcinogenic process. Copyright \u00a9 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2100","type":"journal-article","created":{"date-parts":[[2006,12,6]],"date-time":"2006-12-06T10:17:10Z","timestamp":1165400230000},"page":"314-322","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Comparison of p16<sup>INK4a<\/sup> expression with p53 alterations in head and neck cancer by tissue microarray analysis"],"prefix":"10.1002","volume":"211","author":[{"given":"S","family":"Karsai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"U","family":"Abel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Roesch\u2010Ely","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Affolter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Hofele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Joos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"PK","family":"Plinkert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"FX","family":"Bosch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,12,6]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90214-7"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80452-3"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81400-2"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/366704a0"},{"key":"e_1_2_6_6_2","first-page":"635","article-title":"Cloning and characterization of murine p16INK4a and p15INK4b genes","volume":"11","author":"Quelle DE","year":"1995","journal-title":"Oncogene"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80441-9"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.906"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11698"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.2005.00365.x"},{"key":"e_1_2_6_11_2","first-page":"3855","article-title":"Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis","volume":"59","author":"De Marzo AM","year":"1999","journal-title":"Cancer Res"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201690"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4899-3115-3"},{"volume-title":"Categorical Data Analysis using the SAS\u00ae System","year":"1995","author":"Stokes ME","key":"e_1_2_6_14_2"},{"key":"e_1_2_6_15_2","first-page":"1767","article-title":"Methylation, a major mechanism of p16\/CDKN2 gene inactivation in head and neck squamous carcinoma","volume":"151","author":"El\u2010Naggar AK","year":"1997","journal-title":"Am J Pathol"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6217"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203003"},{"key":"e_1_2_6_18_2","first-page":"2886","article-title":"Elevated p16 at senescence and loss of p16 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells","volume":"56","author":"Reznikoff CA","year":"1996","journal-title":"Cancer Res"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.14.5157-5172.2002"},{"key":"e_1_2_6_20_2","first-page":"4189","article-title":"Expression of mutated p53 occurs in tumor\u2010distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors","volume":"53","author":"Nees M","year":"1993","journal-title":"Cancer Res"},{"key":"e_1_2_6_21_2","first-page":"2488","article-title":"Genetic progression model for head and neck cancer: implications for field cancerization","volume":"56","author":"Califano J","year":"1996","journal-title":"Cancer Res"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10138"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201309"},{"key":"e_1_2_6_24_2","first-page":"6579","article-title":"p53\u2010mediated repression of DNA methyltransferase 1 expression by specific DNA binding","volume":"63","author":"Peterson EJ","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2744(199906)25:2<113::AID-MC6>3.0.CO;2-D"},{"key":"e_1_2_6_26_2","first-page":"1199","article-title":"Genetic evidence in melanoma and bladder cancers that p16INK4 a and p53 function in separate pathways of tumour suppression","volume":"146","author":"Gruis NA","year":"1995","journal-title":"Am J Pathol"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202501"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.22.1841"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1431692100"},{"key":"e_1_2_6_30_2","first-page":"2810","article-title":"Cyclin D1 and p16INK4a expression predict reduced survival in carcinoma of the anterior tongue","volume":"5","author":"Bova RJ","year":"1999","journal-title":"Clin Cancer Res"},{"key":"e_1_2_6_31_2","first-page":"2177","article-title":"Loss of p16 expression has prognostic significance in human nasopharyngeal carcinoma","volume":"9","author":"M\u00e4kitie AA","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200203000-00013"},{"key":"e_1_2_6_33_2","first-page":"5","article-title":"Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control","volume":"58","author":"Andl T","year":"1998","journal-title":"Cancer Res"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63871-0"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0448"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.55.1.58"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00223-X"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.2100","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.2100","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:16:41Z","timestamp":1761059801000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.2100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,12,6]]},"references-count":36,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2007,2]]}},"alternative-id":["10.1002\/path.2100"],"URL":"https:\/\/doi.org\/10.1002\/path.2100","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"type":"print","value":"0022-3417"},{"type":"electronic","value":"1096-9896"}],"subject":[],"published":{"date-parts":[[2006,12,6]]},"assertion":[{"value":"2006-07-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-09-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-12-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}