{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:26:01Z","timestamp":1787682361550,"version":"build-2784847793"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University of Bergen"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Immunol Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) haploinsufficiency is an inborn error of immunity characterized by immune dysregulation, autoimmunity, lymphoproliferation, and an increased risk of malignancy. While susceptibility to oncogenic viral infections has been proposed, the relationship between CTLA-4 haploinsufficiency and human papillomavirus (HPV)-driven carcinogenesis remains poorly characterized. We describe a patient with CTLA-4 haploinsufficiency who developed multiple HPV-associated malignancies. Clinical, pathological, virological, and genetic data were reviewed. Germline genetic testing was performed using whole-exome sequencing, and HPV DNA analysis was conducted on available tumor specimens. A man with a history of alopecia totalis and autoimmune thyroiditis developed five distinct malignancies by the age of 50\u00a0years, including Epstein\u2013Barr virus (EBV)-associated gastric Hodgkin lymphoma, cutaneous squamous cell carcinoma (SCC), and three independent HPV16-positive SCCs involving the oral cavity, anus, and penis. Germline testing identified CTLA-4 haploinsufficiency caused by a likely pathogenic\n                    <jats:italic>CTLA4<\/jats:italic>\n                    variant, c.406C\u2009&gt;\u2009T (p.Pro136Ser). No additional germline variants associated with hereditary cancer predisposition were detected. HPV DNA analysis demonstrated HPV16 positivity in all three mucosal SCCs. This case expands the spectrum of malignancies associated with CTLA-4 haploinsufficiency and suggests that persistent high-risk HPV infection may represent an underrecognized complication of this disorder. The occurrence of three independent HPV16-positive SCCs raises the possibility that CTLA-4 deficiency predisposes to HPV-driven carcinogenesis and supports further investigation of HPV surveillance and cancer prevention strategies in affected individuals.\n                  <\/jats:p>","DOI":"10.1007\/s12026-026-09830-x","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:15:52Z","timestamp":1787634952000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multifocal HPV16-positive squamous cell carcinomas in CTLA-4 haploinsufficiency: expanding the spectrum of virus-associated malignancies"],"prefix":"10.1007","volume":"74","author":[{"given":"Christian Arvei","family":"Moen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin Greve-Isdahl","family":"Mohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thea E. Hetland","family":"Falkenthal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Julieb\u00f8-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J\u00f8rgen","family":"Aarstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svein Erik","family":"Moe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Beisland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Elena","family":"Costea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabet","family":"Ognedal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirik","family":"Bratland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegunn H\u00f8berg","family":"Vetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Berget","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"9830_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209\u201349.","journal-title":"CA Cancer J Clin"},{"key":"9830_CR2","doi-asserted-by":"publisher","first-page":"1112513","DOI":"10.3389\/fimmu.2023.1112513","volume":"14","author":"RV Hewavisenti","year":"2023","unstructured":"Hewavisenti RV, Arena J, Ahlenstiel CL, Sasson SC. Human papillomavirus in the setting of immunodeficiency: Pathogenesis and the emergence of next-generation therapies to reduce the high associated cancer risk. Front Immunol. 2023;14:1112513.","journal-title":"Front Immunol"},{"key":"9830_CR3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/imr.12721","volume":"287","author":"N Mitsuiki","year":"2019","unstructured":"Mitsuiki N, Schwab C, Grimbacher B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev. 2019;287:33\u201349.","journal-title":"Immunol Rev"},{"key":"9830_CR4","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1126\/science.1255904","volume":"345","author":"HS Kuehn","year":"2014","unstructured":"Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345:1623\u20137.","journal-title":"Science"},{"key":"9830_CR5","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1038\/nm.3746","volume":"20","author":"D Schubert","year":"2014","unstructured":"Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20:1410\u20136.","journal-title":"Nat Med"},{"key":"9830_CR6","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1016\/j.jaci.2018.02.055","volume":"142","author":"C Schwab","year":"2018","unstructured":"Schwab C, Gabrysch A, Olbrich P, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142:1932\u201346.","journal-title":"J Allergy Clin Immunol"},{"key":"9830_CR7","doi-asserted-by":"publisher","first-page":"2012","DOI":"10.3389\/fimmu.2018.02012","volume":"9","author":"D Egg","year":"2018","unstructured":"Egg D, Schwab C, Gabrysch A, et al. Increased risk for malignancies in 131 affected CTLA4 mutation carriers. Front Immunol. 2018;9:2012.","journal-title":"Front Immunol"},{"key":"9830_CR8","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1093\/carcin\/bgm043","volume":"28","author":"TH Su","year":"2007","unstructured":"Su TH, Chang TY, Lee YJ, et al. CTLA-4 gene and susceptibility to human papillomavirus-16-associated cervical squamous cell carcinoma in Taiwanese women. 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Written informed consent was obtained from the patient for the publication of case details and images.","order":1,"name":"Ethics","label":"Ethical approval statement","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflicts of interest.","order":2,"name":"Ethics","label":"Disclosure of Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"95"}}