Understanding melanoma biology to improve patient care

Abstract

We have developed mouse models of melanoma driven by human oncogenes and ultraviolet radiation (UVR). These models recapitulate the cardinal pathological and genomic features of human melanoma and begin to reveal how UVR-induced DNA damage cooperates with oncogenes such as V600EBRAF to cause melanoma. By comparing the results from our mouse studies to human melanomas, we have shown that approximately 15% of human common cutaneous melanomas are not driven by UVR. We and others have previously reported that mucosal melanomas are driven by large chromosomal structural variations, but we have recently reported that mucosal melanomas of the conjunctiva are also driven by UVR. These data allow us to postulate that in di?erent microenvironments, melanocytes are subject to speci?c mutational processes that drive melanomagenesis, but that if exposed to UVR, these processes are accelerated. Our data emphasise the importance of also protecting our eyes from the damaging e?ects of UVR and highlight that immunotherapy and targeted therapies could be used for some of the rare forms of melanoma for which they are not currently approved. To re?ne the use of melanoma therapies, we have shown that circulating tumour DNA is a powerful tool for monitoring patient responses to treatment, and we have identi?ed a circulating T cell signature that predicts patient responses to immunotherapy. We have also identi?ed a sub-set of cells that may mediate patient responses to anti-PD1-based immunotherapies. The tools we have developed are exploring how precision immunotherapy could be delivered to melanoma patients