Periodic Reporting for period 4 - MMUVR (Elucidating the role of ultraviolet radiation in melanoma)
Période du rapport: 2020-09-01 au 2021-02-28
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) from the sun, but also from 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 within the skin and to promote inflammation (swelling, redness and sunburn). It is also known that the genetic makeup of an individual (their family genetic history) and their level of pigmentation (dark skin compared to fair skin, red hair or albinos), or those with genetic conditions such as the one called xeroderma pigmentosum (an inherited condition where people cannot repair the damage caused 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 potentially deadly 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. This provided an unprecedented opportunity to investigate how UV light exposure affects melanoma onset and progression. Using different types of UV light and exposure patterns, we confirmed that UV light can accelerate melanoma development in adult mice. Surprisingly, just a single dose of UV light was enough to cause the acceleration, and the mice exposed to UV light generally developed multiple melanomas. In human melanoma and in our mouse melanomas UV light causes a specific pattern of genetic damage, and by comparing our mouse melanomas to human melanomas, we discovered that about 85% of melanomas that arise on the skin of humans are likely to be caused by UV light, but about 15% are not caused by UV light. Surprisingly, in our mice once the melanomas had developed, those that were not associated with exposure to UV light seemed to kill the mice more quickly. The mirroring of our mouse data with the human data, were published in a leading international journal, and since our findings allow us to distinguish, at the genetic level, two subsets of melanoma, they could impact the clinical management of these distinct genetic diseases.
In another study, also published in a leading international journal, we discovered that some rare types of melanoma that arise not in the skin but on the mucosal tissues that line the mouth, eyes, nasal passages and gastrointestinal and genitourinary tracts, can also be divided, genetically, into two subsets – those that carry a pattern of genetic damage cause by UV light, and those that do not. To date, these rare types of melanoma were not thought to be caused by UV light damage, but our findings have implications for their treatment, because it suggests that some of these patients may benefit from treatments that have shown to work in common cutaneous melanoma.
To understand better how UV light exposure and certain genetic features contribute to melanoma development and progression, we tested how changes in these genetic features affect the course of melanoma in our UV light-driven model. We have published our findings about how deficiency of one such gene called MAP3K1, may play a role in accelerating the onset of melanoma, and have submitted a manuscript for publication describing more than one way in which alterations in an important melanoma gene called NRAS in combination with long term UV light exposure, may give rise to melanoma. This has implications for how melanoma develops in older patients.
We have also explored whether and how skin tone influences melanoma development, and what happens when cells cannot repair the genetic damage caused by UV light. Our findings shed light on why fair skinned people with red hair are more susceptible to melanoma development, and have also increased our understanding about the role of UV light and the development of melanoma in people with albinism. Finally, our studies are increasing our understanding of the relative contribution that UV light-induced genetic damage and sunburn damage (inflammation, reddening) make to the initiation and development of melanoma. We have presented this data at various conferences and are preparing manuscripts describing our findings for publication.
The data generated by this project is informing public health messaging, allowing us to make more accurate predictions about the course of melanoma in particular human populations, and helping clinicians and researchers to develop better treatment and prevention strategies.
In another study, also published in a leading international journal, we discovered that some rare types of melanoma that arise not in the skin but on the mucosal tissues that line the mouth, eyes, nasal passages and gastrointestinal and genitourinary tracts, can also be divided, genetically, into two subsets – those that carry a pattern of genetic damage cause by UV light, and those that do not. To date, these rare types of melanoma were not thought to be caused by UV light damage, but our findings have implications for their treatment, because it suggests that some of these patients may benefit from treatments that have shown to work in common cutaneous melanoma.
To understand better how UV light exposure and certain genetic features contribute to melanoma development and progression, we tested how changes in these genetic features affect the course of melanoma in our UV light-driven model. We have published our findings about how deficiency of one such gene called MAP3K1, may play a role in accelerating the onset of melanoma, and have submitted a manuscript for publication describing more than one way in which alterations in an important melanoma gene called NRAS in combination with long term UV light exposure, may give rise to melanoma. This has implications for how melanoma develops in older patients.
We have also explored whether and how skin tone influences melanoma development, and what happens when cells cannot repair the genetic damage caused by UV light. Our findings shed light on why fair skinned people with red hair are more susceptible to melanoma development, and have also increased our understanding about the role of UV light and the development of melanoma in people with albinism. Finally, our studies are increasing our understanding of the relative contribution that UV light-induced genetic damage and sunburn damage (inflammation, reddening) make to the initiation and development of melanoma. We have presented this data at various conferences and are preparing manuscripts describing our findings for publication.
The data generated by this project is informing public health messaging, allowing us to make more accurate predictions about the course of melanoma in particular human populations, and helping clinicians and researchers to develop better treatment and prevention strategies.
Our studies have revealed a clinically relevant distinction between melanomas bearing different patterns of genetic damage that has not been previously defined. The project has provided 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 new tools to counteract this damage. Our experimental systems will also allow us and others to explore new therapies for melanoma and to use the information to generate better predictive tools for who may respond to treatments and who is unlikely to benefit.