{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:42:25Z","timestamp":1784641345340,"version":"3.55.0"},"reference-count":68,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2017,3,13]],"date-time":"2017-03-13T00:00:00Z","timestamp":1489363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["TL1TR000141"],"award-info":[{"award-number":["TL1TR000141"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2017,5,15]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The incidence of human papillomavirus (HPV)\u2010associated (HPV\u2010positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise. Newly diagnosed HPV\u2010positive HNSCCs in the United States currently outnumber any other HPV\u2010associated cancers, including cervical cancer. Despite introduction of the HPV vaccine, the epidemic of HPV\u2010positive HNSCC is expected to continue for approximately 60 years. Compared with patients who have tobacco\u2010associated HNSCC, those who have HPV\u2010positive HNSCC have better overall survival and response to treatment. Current treatment, including chemotherapy and radiation therapy, is associated with lifelong morbidity, and there are limited treatments and no curative options for patients who develop recurrent metastatic disease. Therapeutic de\u2010escalation (decreased radiation dose) is being tested through clinical trials; however, those studies select patients based solely on tumor and patient smoking characteristics. Mechanisms of HPV\u2010driven carcinogenesis in HNSCC are not well understood, which limits new therapeutic strategies and hinders the appropriate selection of patients for de\u2010escalation therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>The authors analyzed HNSCC data from The Cancer Genome Atlas to identify molecular characteristics that correlate with outcomes and integration status of the HPV genome.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The current investigations identified a subset of HPV\u2010positive HNSCCs with mutations in the genes <jats:italic>TRAF3<\/jats:italic> (tumor necrosis factor receptor\u2010associated factor 3) and <jats:italic>CYLD<\/jats:italic> (cylindromatosis lysine 63 deubiquitinase). Defects in <jats:italic>TRAF3<\/jats:italic> and <jats:italic>CYLD<\/jats:italic> correlated with the activation of transcriptional factor nuclear factor \u03baB, episomal HPV status of tumors, and improved patient survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Defects in <jats:italic>TRAF3<\/jats:italic>\/<jats:italic>CYLD<\/jats:italic> were accompanied with the activation of nuclear factor \u03baB signaling and maintenance of episomal HPV in tumors, suggesting that these mutations may support an alternative mechanism of HPV tumorigenesis in head and neck tumors. <jats:bold><jats:italic>Cancer<\/jats:italic> 2017;123:1778\u20131790<\/jats:bold>. \u00a9 <jats:italic>2017 The Authors<\/jats:italic>. <jats:italic>Cancer<\/jats:italic> published by Wiley Periodicals, Inc. on behalf of <jats:italic>American Cancer Society<\/jats:italic>. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.30570","type":"journal-article","created":{"date-parts":[[2017,3,14]],"date-time":"2017-03-14T14:28:02Z","timestamp":1489501682000},"page":"1778-1790","source":"Crossref","is-referenced-by-count":106,"title":["<i>TRAF3\/CYLD<\/i> mutations identify a distinct subset of human papillomavirus\u2010associated head and neck squamous cell carcinoma"],"prefix":"10.1002","volume":"123","author":[{"given":"Michael","family":"Hajek","sequence":"first","affiliation":[{"name":"Division of Otolaryngology Department of Surgery, Yale University New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Sewell","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology Department of Surgery, Yale University New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Kaech","sequence":"additional","affiliation":[{"name":"Department of Immunobiology Yale University New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Burtness","sequence":"additional","affiliation":[{"name":"Yale Cancer Center Yale School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendell G.","family":"Yarbrough","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology Department of Surgery, Yale University New Haven Connecticut"},{"name":"Yale Cancer Center Yale School of Medicine New Haven Connecticut"},{"name":"Department of Pathology Yale School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Issaeva","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology Department of Surgery, Yale University New Haven Connecticut"},{"name":"Yale Cancer Center Yale School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1549"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21349"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22963"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0912217"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.61.6995"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2015.0102"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.101"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90409-8"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb08594.x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2003.11.035"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2004.08.021"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14129"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416074111"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2998"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00703-1"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2008.08.007"},{"key":"e_1_2_7_18_1","first-page":"3495","article-title":"The host environment promotes the constitutive activation of nuclear factor\u2010kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma","volume":"59","author":"Dong G","year":"1999","journal-title":"Cancer Res."},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-0852"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-3047"},{"key":"e_1_2_7_21_1","first-page":"1369","article-title":"Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer","volume":"5","author":"Chen Z","year":"1999","journal-title":"Clin Cancer Res."},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800372"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.03.008"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2012.01100.x"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.07.004"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.07.003"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004088"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.892"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04374"},{"key":"e_1_2_7_33_1","first-page":"2243","article-title":"CD40\u2010induced growth inhibition in epithelial cells is mimicked by Epstein\u2010Barr virus\u2010encoded LMP1: involvement of TRAF3 as a common mediator","volume":"13","author":"Eliopoulos AG","year":"1996","journal-title":"Oncogene."},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01993-10"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003384"},{"issue":"11","key":"e_1_2_7_36_1","first-page":"2646","article-title":"TRAF3 signaling: competitive binding and evolvability of adaptive viral molecular mimicry","author":"Guven\u2010Maiorov E","year":"1860","journal-title":"Biochim Biophys Acta"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2003152"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep13128"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2016.45"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002165"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.12.003"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/PDM.0b013e3181ba2d96"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1768"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-3310"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2008.136"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2011.42"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1607606113"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2007.04.082"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2585"},{"key":"e_1_2_7_50_1","first-page":"677","article-title":"Relationship between smoking, HPV infection, and risk of cervical cancer","volume":"36","author":"Mzarico E","year":"2015","journal-title":"Eur J Gynaecol Oncol."},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1983.03340040056033"},{"key":"e_1_2_7_52_1","first-page":"2011","article-title":"Smoking and cervical cancer","volume":"847684","author":"Fonseca\u2010Moutinho JA","year":"2011","journal-title":"ISRN Obstet Gynecol"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa065497"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3619"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.2217\/fvl.16.2"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/v5112624"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2005.09.002"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1128\/CDLI.8.2.209-220.2001"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.7.5654-5660.1998"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103408200"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg267"},{"key":"e_1_2_7_62_1","first-page":"345","article-title":"Overexpression of EGR\u20101 modulates the activity of NF\u2010kappaB and AP\u20101 in prostate carcinoma PC\u20103 and LNCaP cell lines","volume":"39","author":"Parra E","year":"2011","journal-title":"Int J Oncol."},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.251"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210700"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-06-0455"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR3039"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.2307\/3579402"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809242105"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308102100"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.30570","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.30570","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cncr.30570","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.30570","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T13:08:41Z","timestamp":1760274521000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.30570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,13]]},"references-count":68,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2017,5,15]]}},"alternative-id":["10.1002\/cncr.30570"],"URL":"https:\/\/doi.org\/10.1002\/cncr.30570","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,13]]}}}