The gene-gene and gene-environment interactions in melanoma

Abstract

Cutaneous melanoma is the most deadly form of skin cancer. The protein kinase BRAF is mutated in approximately 50% of melanomas, and the most common somatic mutation results in a V600E amino acid change. By itself, V600EBRAF supports signal independent growth and drives the proliferation of melanocytes. However, this is insufficient to drive the full malignant process, and the majority of V600EBRAF-expressing melanocytes senesce. As such, additional genetic or environmental events must co-occur with oncogenic BRAF to drive the progression of melanocytes to melanoma.The nature of the interaction between V600EBRAF-expressing melanocytes and their surrounding microenvironment is complex and highly sensitive to internal and external selection pressures. By using a genetically engineered mouse model of melanoma, where the expression of V600EBRAF can be conditionally induced in a spatial and temporally restricted manner, I have been able to elucidate some of the gene-gene and gene-environment interactions in melanoma. Expression of V600EBRAF in the melanocytic lineage of adult mice results in the majority of mice developing long latency melanoma. By modifying the genetic and environmental surroundings of these mice I have been able to investigate factors that affect the latency of melanoma.Exposure to ultraviolet radiation (UVR) is the most important environmental risk factor in melanoma, and amongst other functions, it activates the stress kinase pathway. By genetically modifying the transcriptional function of members of this signalling cascade, I describe that ATF2, a stress kinase, behaves as an oncogene in V600EBRAF-driven melanoma. Although exposure to UVR is epidemiologically linked to melanoma, the mechanisms by which UVR increases melanoma risk remain elusive. I investigated the wavelengths of UVR that are important in conferring risk, and by altering the timing and recurrence of UVR exposure in this mouse model, I demonstrate that the progression of melanocytes to melanoma is sensitive to both mutation burden and mutation context. Ultimately, by using genetically engineered mouse model of melanoma, I reveal new insights into the role of UVR in melanomagenesis, and describe novel oncogenic targets in this disease. 

Date of Award	31 Dec 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Iain Hagan (Supervisor) & Richard Marais (Supervisor)