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Elucidating the role of ultraviolet radiation in melanoma

Periodic Reporting for period 3 - MMUVR (Elucidating the role of ultraviolet radiation in melanoma)

Reporting period: 2019-03-01 to 2020-08-31

Melanoma incidence continues to rise across Europe and compared to other cancers, melanoma disproportionately affects young people, causing a significant loss of life-years in those affected.
Ultraviolet light (UV light) both from the sun and sunbeds is the most significant environmental risk factor for melanoma. It is widely accepted that the potential of UV light to promote tumour development in the skin resides in its ability to damage the genetic material of cells in the skin and promote inflammation (swelling and redness or sunburn).
It is also known that the genetic makeup of an individual (presence melanoma family genes, pigmentation – albinism or red hair, or xeroderma pigmentosum - a condition whereby patients’ cells cannot repair the damage inflicted by UV light) also plays an important role in the development of melanoma. However, our knowledge of how the interactions between particular genetic features and UV light lead to melanoma is still very limited. Our goal is to investigate the relative contributions of UV light and genetic characteristics to melanoma initiation and progression and by revealing the nature of their interactions, inform prevention strategies and the clinical management of this disease.
At the start of our project, we had already developed a mouse model of UV light-driven melanoma, which faithfully mimicked UV light-driven melanoma in humans, and therefore provided an unprecedented opportunity to dissect how UVR exposure affects melanoma onset and progression. Using different UV light wavelengths and exposure patterns, we made the surprising discovery that animals carrying tumours with a very specific pattern of genetic damage known to be caused by UV light had a better overall survival than those where this pattern was absent. We saw these results mirrored in human data, and our findings will shortly be published in a leading international journal. Because our findings allow us to distinguish, at the genetic level, two subsets of melanoma, they could impact the clinical management of these subtypes.
To better understand how UV light exposure and certain genetic features contribute to melanoma development and progression, we are testing how changes in these genetic features affect the course of melanoma in our UV light-driven model. We will address questions about whether and how pigment genes influence melanoma development, and what happens when cells cannot repair genetic damage caused by UV light. This will reveal whether we can make predictions about the course of melanoma in particular patient populations, and how best to target prevention strategies.
Thus far, our studies have revealed a clinically relevant distinction between melanomas bearing different patterns of genetic damage that has not been previously defined. Our current lines of investigation are providing a deeper understanding of how damage from UV light can influence the course of disease in patients with particular genetic characteristics, and may ultimately provide us with tools to counteract this damage.