Subramanian, Priya; (2024) The role of p16 in senescence, immunity and cutaneous melanoma development. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text Subramanian_Thesis.pdf - Other Download (101MB) | Preview

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.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item