{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T20:05:23Z","timestamp":1776456323654,"version":"3.51.2"},"reference-count":7,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Med Case Reports"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Aggressive squamous cell carcinomas (SCCs) present frequently in the context of chronic skin injury occurring in patients with the congenital blistering disease recessive dystrophic epidermolysis bullosa. Recently, these cancers were shown to harbor mutation signatures associated with endogenous deaminases of the active polynucleotide cytosine deaminase family, collectively termed APOBEC, and  clock-like COSMIC\u00a0[Catalogue of Somatic Mutations in Cancer] signatures, which are associated with normal aging and might result from cumulative DNA replication errors. We present a case of a nasal septal SCC arising in the context of recurrent injury, but also modest past tobacco use. Our genetic analysis of this tumor reveals unusually high APOBEC and  clock-like\u00a0but low tobacco-related COSMIC signatures, suggesting that chronic injury may have played a primary role in somatic mutation. This case report demonstrates how signature-based analyses may implicate key roles for certain mutagenic forces in individual malignancies such as head-and-neck SCC, with multiple etiological origins.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>We report the case of a 43-year-old male former smoker who presented with congestion and swelling following a traumatic nasal fracture. During surgery, the mucosa surrounding the right nasal valve appeared abnormal, and biopsies revealed invasive keratinizing SCC. Frozen section biopsies revealed multiple areas to be positive for SCC. Gene sequencing showed loss of <jats:italic>PTEN<\/jats:italic> (exons 2\u20138), <jats:italic>CDKN2A\/B<\/jats:italic> and <jats:italic>TP53<\/jats:italic> (exons 8\u20139), <jats:italic>MYC<\/jats:italic> amplification, and <jats:italic>BLM S338<\/jats:italic>*. Exome sequencing data also revealed that 36% of mutations matched an APOBEC mutational signature (COSMIC signatures 2 and 13) and 53% of mutations matched the  clock-like\u00a0mutation signature (COSMIC signature 5). These proportions place this tumor in the 90th percentile bearing each signature, independently, in a reference data set combining cutaneous and The Cancer Genome Atlas (TCGA) head and neck SCC data. In contrast, few mutations harbored a tobacco-related COSMIC signature 4, representing about the 10th percentile in our reference SCC data set. The patient was treated with partial rhinectomy with local flap reconstruction, bilateral neck dissection, and adjuvant radiation therapy; the patient remains disease-free to date.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Based on comparative mutational signature analysis, we propose that the history of tobacco use and traumatic injury may have collaborated in activating APOBEC enzymes and the  clock-like\u00a0mutational process, ultimately leading to cancer formation. Clinical awareness of the relationship between epithelial injury and tumorigenesis should enhance earlier detection of this particularly aggressive type of cancer.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13256-021-02685-w","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T23:05:51Z","timestamp":1619737551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Elevated APOBEC mutational signatures implicate chronic injury in etiology of an aggressive head-and-neck squamous cell carcinoma: a case report"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4609-3631","authenticated-orcid":false,"given":"Jena","family":"Patel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoline Y.","family":"den Breems","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madalina","family":"Tuluc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph M","family":"Curry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew P.","family":"South","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond J.","family":"Cho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,30]]},"reference":[{"key":"2685_CR1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1126\/scitranslmed.aas9668","volume":"10","author":"RJ Cho","year":"2018","unstructured":"Cho RJ, Alexandrov LB, Breems NYD, Atanasova VS, Farshchian M, Purdom E, et al. APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. Sci Transl Med. 2018;10:455.","journal-title":"Sci Transl Med"},{"issue":"9","key":"2685_CR2","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.jgg.2017.04.009","volume":"44","author":"B Yang","year":"2017","unstructured":"Yang B, Li X, Lei L, Chen J. APOBEC: From mutator to editor. J Genet Genomics. 2017;44(9):423\u201337.","journal-title":"J Genet Genomics."},{"key":"2685_CR3","doi-asserted-by":"crossref","unstructured":"Alexandrov LB, Ju YS, Haase K, Loo PV, Martincorena I, Nik-Zainal S, et al. Mutational signatures associated with tobacco smoking in human cancer. Sci Mag. 2016.","DOI":"10.1101\/051417"},{"issue":"12","key":"2685_CR4","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1038\/ng.3441","volume":"47","author":"LB Alexandrov","year":"2015","unstructured":"Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, et al. Clock-like mutational processes in human somatic cells. Nat Genet. 2015;47(12):1402\u20137.","journal-title":"Nat Genet"},{"key":"2685_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13059-016-0893-4","volume":"17","author":"R Rosenthal","year":"2016","unstructured":"Rosenthal R, Mcgranahan N, Herrero J, Taylor BS, Swanton C. DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Biol. 2016;17:1.","journal-title":"Genome Biol"},{"issue":"9","key":"2685_CR6","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1038\/ng.2702","volume":"45","author":"SA Roberts","year":"2013","unstructured":"Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet. 2013;45(9):970\u20136.","journal-title":"Nat Genet"},{"issue":"5","key":"2685_CR7","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1021\/acs.biochem.8b00858","volume":"58","author":"MV Kvach","year":"2018","unstructured":"Kvach MV, Barzak FM, Harjes S, Schares HAM, Jameson GB, Ayoub AM, et al. Inhibiting APOBEC3 Activity with Single-Stranded DNA Containing 2\u2032-Deoxyzebularine Analogues. Biochemistry. 2018;58(5):391\u2013400.","journal-title":"Biochemistry"}],"container-title":["Journal of Medical Case Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13256-021-02685-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13256-021-02685-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13256-021-02685-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T13:03:57Z","timestamp":1621947837000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmedicalcasereports.biomedcentral.com\/articles\/10.1186\/s13256-021-02685-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,30]]},"references-count":7,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2685"],"URL":"https:\/\/doi.org\/10.1186\/s13256-021-02685-w","relation":{},"ISSN":["1752-1947"],"issn-type":[{"value":"1752-1947","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,30]]},"assertion":[{"value":"24 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 May 2021","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The Family Name and Given Name of an author was interchanged, this article has been updated","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Patient consent was obtained for the study of their tissue and use of their health data for the purposes of this manuscript. Consent form is available upon request.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"252"}}