{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T16:53:08Z","timestamp":1775494388948,"version":"3.50.1"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T00:00:00Z","timestamp":1622678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Laryngoscope Investig Oto"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Patients with laryngeal squamous cell carcinoma (LSCC) often fail radiation therapy (RT), when received as monotherapy or in combination with other treatment modalities. Mechanisms for RT failure are poorly understood. We hypothesized that tumors failing RT would have increased rates of somatic mutations in genes associated with radiation resistance, particularly in genes associated with the <jats:italic>NFE2L2<\/jats:italic> oxidative stress pathway. Using targeted exome sequencing on pretreated LSCC tumors, we retrospectively compared somatic mutation profile with clinical data and response to treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Tumors were classified as either radiation\u2010resistant (RR) or radiation\u2010sensitive (RS). RR was defined as persistent or recurrent disease within 2\u2009years of receiving full\u2010dose RT. Early stage (ES) LSCC was defined as Stage I or II tumors without lymph node involvement. Eight genes associated with radiation resistance were prioritized for analysis. RT\u2010qPCR was performed on five <jats:italic>NFE2L2<\/jats:italic> pathway genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty LSCC tumors were included and classified as either RR (n\u00a0=\u00a08) or RS (n\u00a0=\u00a012). No differences in individual rates of somatic mutations by genes associated with radiation resistance were identified. Higher rates of total mutational burden (TMB) and increased alterations associated with the <jats:italic>NFE2L2<\/jats:italic> pathway was observed in RR vs RS tumors (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.05). In an analysis of only ES\u2010LSCC patients (RR, n\u00a0=\u00a03 and RS, n\u00a0=\u00a03), RR tumors had increased NFE2L2 somatic pathway mutations (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.014) and increased <jats:italic>NQO1<\/jats:italic> mRNA expression (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Increased TMB and <jats:italic>NFE2L2<\/jats:italic> pathway alterations were associated with radiation resistance in LSCC. <jats:italic>NQO1<\/jats:italic> mRNA expression may serve as a biomarker for RT response in ES\u2010LSCC.<\/jats:p><jats:p>Level of Evidence: II1.<\/jats:p><\/jats:sec>","DOI":"10.1002\/lio2.588","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T09:36:20Z","timestamp":1622799380000},"page":"699-707","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Correlation of alterations in the <i><scp>KEAP1<\/scp>\/<scp>CUL3<\/scp>\/<scp>NFE2L2<\/scp><\/i> pathway with radiation failure in larynx squamous cell carcinoma"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-2309","authenticated-orcid":false,"given":"Siddharth","family":"Sheth","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas R.","family":"Farquhar","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8297-3329","authenticated-orcid":false,"given":"Travis P.","family":"Schrank","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Department of Cell Biology and Physiology The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wesley","family":"Stepp","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Mazul","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Washington University in Saint Louis, School of Medicine  St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Hayward","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2126-6663","authenticated-orcid":false,"given":"Nicholas","family":"Lenze","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Little","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heejoon","family":"Jo","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology, Department of Medicine University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Ben","family":"Major","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhishamjit S.","family":"Chera","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9111-6767","authenticated-orcid":false,"given":"Jose P.","family":"Zevallos","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Washington University in Saint Louis, School of Medicine  St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. Neil","family":"Hayes","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology, Department of Medicine University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,6,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21654"},{"issue":"6","key":"e_1_2_8_3_1","first-page":"603","article-title":"Treatment of early\u2010stage glottic cancer: meta\u2010analysis comparison of laser excision versus radiotherapy","volume":"38","author":"Higgins KM","year":"2009","journal-title":"J Otolaryngol Head Neck Surg"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.04.1954"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23504"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.132.1.59"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0347(199605\/06)18:3<229::AID-HED4>3.0.CO;2-1"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1067\/mhn.2003.63"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2012.10.022"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-014-0990-8"},{"issue":"8","key":"e_1_2_8_11_1","first-page":"13235","article-title":"Correlation between expression of NF\u2010E2\u2010related factor 2 and progression of gastric cancer","volume":"8","author":"Bao J","year":"2015","journal-title":"Int J Clin Exp Med"},{"issue":"4","key":"e_1_2_8_12_1","first-page":"1502","article-title":"Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma","volume":"7","author":"Bao LJ","year":"2014","journal-title":"Int J Clin Exp Pathol"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1008-4"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-014-3600-2"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-015-4747-6"},{"issue":"2","key":"e_1_2_8_16_1","first-page":"38","article-title":"Radiogenomics offers promise of personalized radiation cancer therapy","volume":"29","author":"Becze E","year":"2014","journal-title":"ONS Connect"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1053-4296(05)80034-7"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/09553009414550041"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.09.006"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2012.10.001"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2443.2010.01473.x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14129"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1655"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4400"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23663"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5003"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.06.082"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0127"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1193-3"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056823"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2006.02.009"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-8140(97)01904-X"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.3109\/02841869509094031"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0360-3016(97)00101-6"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.21983"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1088\/0031-9155\/49\/16\/021"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0360-3016(02)02936-X"}],"container-title":["Laryngoscope Investigative Otolaryngology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lio2.588","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/lio2.588","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lio2.588","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T13:02:28Z","timestamp":1693314148000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/lio2.588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,3]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1002\/lio2.588"],"URL":"https:\/\/doi.org\/10.1002\/lio2.588","archive":["Portico"],"relation":{},"ISSN":["2378-8038","2378-8038"],"issn-type":[{"value":"2378-8038","type":"print"},{"value":"2378-8038","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,3]]},"assertion":[{"value":"2021-03-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}