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Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the <jats:italic>CDKN2A<\/jats:italic> gene coding for the cyclin inhibitor p16<jats:sup>INK4a<\/jats:sup>. Melanocytes within skin biopsies from FMS patients express significantly less p16<jats:sup>INK4a<\/jats:sup> but express higher levels of the DNA\u2010damage protein \ud835\udefeH2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in\u00a0vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in\u00a0vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence\u2010related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in\u00a0vivo.<\/jats:p>","DOI":"10.1111\/acel.14373","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T04:45:43Z","timestamp":1729226743000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multiple outcomes of the germline <scp>p16<sup>INK4a<\/sup><\/scp> mutation affecting senescence and immunity in human skin"],"prefix":"10.1111","volume":"24","author":[{"given":"Priya","family":"Subramanian","sequence":"first","affiliation":[{"name":"Division of Medicine University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5266-9393","authenticated-orcid":false,"given":"Souraya","family":"Sayegh","sequence":"additional","affiliation":[{"name":"Division of Medicine University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phatthamon","family":"Laphanuwat","sequence":"additional","affiliation":[{"name":"Division of Medicine University College London  London UK"},{"name":"Department of Pharmacology, Faculty of Medicine Khon Kaen University  Khon Kaen Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7621-9699","authenticated-orcid":false,"given":"Oliver P.","family":"Devine","sequence":"additional","affiliation":[{"name":"Division of Medicine University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Henrique","family":"Fantecelle","sequence":"additional","affiliation":[{"name":"N\u00facleo de Doen\u00e7as Infecciosas Universidade Federal Do Esp\u00edrito Santo  Vit\u00f3ria Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Sikora","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0990-8835","authenticated-orcid":false,"given":"Emma S.","family":"Chambers","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia N.","family":"Karagiannis","sequence":"additional","affiliation":[{"name":"St. John's Institute for Dermatology, School of Basic and Medical Biosciences, King's College London, Guy's Hospital  London UK"},{"name":"Breast Cancer Now Research Unit School of Cancer &amp; Pharmaceutical Sciences, Guy's Cancer Centre, King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C. 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