The Role of Ultraviolet Radiation-Induced DNA Damage in Melanomagenesis

Abstract

Melanoma is the deadliest form of skin cancer and concerningly its incidence has been steadily increasing over the past 20 years. A combination of epidemiological, genomic sequencing and mouse studies have unequivocally identified the importance of ultraviolet radiation (UVR) in the development of this disease. Despite this, due to a lack of functional studies we do not fully understand the mechanism through which UVR promotes melanomagenesis. Patients with the repair-deficient genetic disorder xeroderma pigmentosum (XP) highlight the relevance specifically of UVR-induced DNA damage. Patients with this disorder have a dramatic increased risk of all types of skin cancer, including melanoma; currently however, molecular sequencing studies to understand melanomagenesis in these patients are limited. Therefore, in this study I first focus specifically on XP derived melanomas, subjecting them to whole exome sequencing to elucidate the mechanism of melanomagenesis in these rare cases. With this analysis I identify mutations in NF1 as the key oncogenic drivers. Furthermore, I also uncover that the specific repair defects in these patients shape the UVR-induced mutation spectrum, thus providing mechanistic insights into their function. I then focussed more broadly on non-XP melanomas to further elucidate the mechanism by which UVR-induced DNA damage contributes to melanomagenesis. UVR induces a heavy mutation burden within melanocytes. However, despite this, the most abundant melanoma driver mutations in BRAF and NRAS are not caused by the archetypal UVR-signature C>T mutation. In my final chapter I undertake bioinformatic analysis of melanoma genomic sequencing to demonstrate that the mutation types causing these key oncogenic mutations, despite not being typical UVR-induced C>Ts, may still be caused by UVR due to alternate errors during the repair process. Alongside this, to mechanistically investigate the importance of UVR-induced DNA damage in either the melanocyte or stromal compartments, I design and utilise novel transgenic mouse models to selectively abrogate UVR-induced repair in specifically the melanocytes or the microenvironment. These models in combination with BRAF melanoma model developed previously in the group identify that UVR-induced DNA damage in both the melanocytes and in the surrounding microenvironment contribute by separate mechanisms to melanoma initiation.

Date of Award	8 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Valeria Pavet Rodriguez (Co Supervisor), Richard Marais (Main Supervisor) & Nathalie Dhomen (Co Supervisor)