TY  - UNPB
UR  - https://discovery.ucl.ac.uk/id/eprint/10186871/
PB  - UCL (University College London)
N2  - 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.
ID  - discovery10186871
A1  - Subramanian, Priya
M1  - Doctoral
Y1  - 2024/02/28/
AV  - public
EP  - 240
TI  - The role of p16 in senescence,  immunity and cutaneous melanoma  development
N1  - 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.
ER  -