eprintid: 10186871 rev_number: 8 eprint_status: archive userid: 699 dir: disk0/10/18/68/71 datestamp: 2024-03-21 11:34:30 lastmod: 2024-03-21 11:34:30 status_changed: 2024-03-21 11:34:30 type: thesis metadata_visibility: show sword_depositor: 699 creators_name: Subramanian, Priya title: The role of p16 in senescence, immunity and cutaneous melanoma development ispublished: unpub divisions: UCL divisions: B02 divisions: C10 divisions: D17 note: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. abstract: Melanoma is an aggressive skin cancer, approximately 3-5% of which arise from an inherited genetic mutation (Goldstein and Tucker 2001; Rossi et al. 2019), most commonly the germline heterozygous CDKN2A mutation. The CDKN2A gene encodes p16, a tumour suppressor. Tumour suppressor mutations are known to result in increased tumours; however it is not understood why most individuals with the CDKN2A mutation mostly manifest cutaneous melanoma. In this study I aimed to examine the cellular basis underlying excess melanomas in people with the CDKN2A mutation by examining cellular senescence and immunity. Consenting patients with the CDKN2A mutation were recruited from the NHS, and healthy donors were recruited as controls from the public. Blood and skin biopsies were taken for the investigation of senescence and immunity characteristics. Donors with the CDKN2A mutation exhibit altered cutaneous senescence features, specifically CDKN2A-melanocytes express less p16 and have fewer telomere associated foci (TAF) than control melanocytes. CDKN2A-melanocytes and fibroblasts can be induced to senescence; however CDKN2A-fibroblasts display delayed replicative senescence when compared to control fibroblasts. When considering immunity, healthy CDKN2A-skin exhibits reduced numbers of T cells when compared to control skin. Patient skin also shows diminished expression of Melan A, a protein exclusively expressed by melanocytes. Cytometric bead array studies in vitro show cutaneous ‘senescent’ fibroblasts from CDKN2A-donors produce less leucocyte chemoattractants (CXCL10, CCL5, IL6) than controls. The germline human CDKN2A-mutation confers a multi-layered deficit underlying the propensity to cutaneous melanoma. Baseline senescence dysregulation likely lowers the threshold for total loss of senescence through ultraviolet radiation-induced DNA damage. The altered chemoattractant secretion from CDKN2A-fibroblasts could result in the recruitment of fewer lymphocytes into the skin of patients at basal steady-state. Moreover, the specific reduction of Melan A, a key antigen in activating anti melanocyte cytotoxicity, alongside reduced lymphocyte numbers could impair destruction of melanocytes in the early stages of tumour formation. These findings suggest potential treatment avenues for people with the CDKN2A mutation, including Melan A vaccination to boost anti-melanocyte antigenicity. date: 2024-02-28 date_type: published oa_status: green full_text_type: other thesis_class: doctoral_open thesis_award: Ph.D language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2236547 lyricists_name: Subramanian, Priya lyricists_id: PSUBR66 actors_name: Subramanian, Priya actors_name: Jayawardana, Anusha actors_id: PSUBR66 actors_id: AJAYA51 actors_role: owner actors_role: impersonator full_text_status: public pages: 240 institution: UCL (University College London) department: Division of Medicine thesis_type: Doctoral citation: Subramanian, Priya; (2024) The role of p16 in senescence, immunity and cutaneous melanoma development. Doctoral thesis (Ph.D), UCL (University College London). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10186871/1/Subramanian_Thesis.pdf