Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Johansson, Peter; Brooks, Kelly; Newell, Felicity; Palmer, Jane M.; Wilmott, James S.; Pritchard, Antonia L.; Broit, Natasa; Wood, Scott; Carlino, Matteo S.; Leonard, Conrad; Koufariotis, Lambros T.; Nathan, Vaishnavi; Beasley, Aaron B.; Howlie, Madeleine; Dawson, Rebecca; Rizos, Helen; Schmidt, Chris; Long, Georgina V.; Hamilton, Hayley; Kiilgaard, Jens Folke; Isaacs, Timothy; Gray, Elin S.; Rolfe, Olivia; Park, John J.; Stark, Andrew; Mann, Graham J.; Scolyer, Richard A.; Pearson, John V.; Baren, Nicolas van; Waddell, Nicola; Wadt, Karin; McGrath, Lindsay A.; Warrier, Sunil; Glasson, William; Hayward, Nicholas K.

doi:10.1038/s41467-020-16276-8

Cited by 96 publications

(113 citation statements)

References 58 publications

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“…In summary, exposure of the eye to sunlight causes cataract, photoconjunctivitis, pterygium macular and retinal degeneration [ 103 , 104 ] and possibly conjunctival and uveal melanoma (UM) [ 77 ]. A recent genetic analysis of UM showed UVR signature mutations (cytosine (C) to thymine (T) transition) in iris melanomas [ 105 ] but no other UM. It is not known if these are passenger or driver mutations.…”

Section: Evidence For Harms To Health From Sun Exposurementioning

confidence: 99%

Insufficient Sun Exposure Has Become a Real Public Health Problem

Alfredsson

Armstrong

Butterfield

et al. 2020

IJERPH

108

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This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer’s disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide from the skin and direct effects of ultraviolet radiation (UVR) on peripheral blood cells. Collectively, this evidence indicates it would be wise for people living outside the tropics to ensure they expose their skin sufficiently to the sun. To minimize the harms of excessive sun exposure, great care must be taken to avoid sunburn, and sun exposure during high ambient UVR seasons should be obtained incrementally at not more than 5–30 min a day (depending on skin type and UV index), in season-appropriate clothing and with eyes closed or protected by sunglasses that filter UVR.

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Section: Evidence For Harms To Health From Sun Exposurementioning

confidence: 99%

Insufficient Sun Exposure Has Become a Real Public Health Problem

Alfredsson

Armstrong

Butterfield

et al. 2020

IJERPH

108

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“…Seventy-one percent of iris tumours have a complete or partial loss of chromosome 3, and some tumours have a chromosome 9 loss [ 80 , 81 ]. Iris melanomas have a relatively high mutation burden compared to other UMs, which is driven by UV radiation [ 82 ]. Immunotherapy, which is helpful in UMs with a MBD4 mutation and a high mutation burden, is therefore probably also useful for iris melanomas, but luckily, these tumours do not often give rise to metastases.…”

Section: Tumour Developmentmentioning

confidence: 99%

Iris Colour and the Risk of Developing Uveal Melanoma

Houtzagers

Wierenga

Ruys

et al. 2020

IJMS

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Uveal melanoma (UM) is a global disease which especially occurs in elderly people. Its incidence varies widely between populations, with the highest incidence among Caucasians, and a South-to-North increase in Europe. As northern Europeans often have blond hair and light eyes, we wondered whether iris colour may be a predisposing factor for UM and if so, why. We compared the distribution of iris colour between Dutch UM patients and healthy Dutch controls, using data from the Rotterdam Study (RS), and reviewed the literature regarding iris colour. We describe molecular mechanisms that might explain the observed associations. When comparing a group of Dutch UM patients with controls, we observed that individuals from Caucasian ancestry with a green/hazel iris colour (Odds Ratio (OR) = 3.64, 95% Confidence Interval (CI) 2.57–5.14) and individuals with a blue/grey iris colour (OR = 1.38, 95% CI 1.04–1.82) had a significantly higher crude risk of UM than those with brown eyes. According to the literature, this may be due to a difference in the function of pheomelanin (associated with a light iris colour) and eumelanin (associated with a brown iris colour). The combination of light-induced stress and aging may affect pheomelanin-carrying melanocytes in a different way than eumelanin-carrying melanocytes, increasing the risk of developing a malignancy.

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“…In contrast to posterior UM, mutations in BRAF (0–47%) and NRAS have been described in iris melanoma, although the frequency of their presence is unclear, and they might not represent driver mutations ( Table 1 ) [ 44 , 45 , 46 , 47 ]. As the iris is not protected from UV damage, UV-induced mutational signatures have recently been detected in iris melanoma [ 48 , 49 ].…”

Section: Genetic Biomarkers At Initial Diagnosis Of the Primary Tumentioning

confidence: 99%

“…Therefore, experience with the treatment of metastatic iris melanoma is scarce, and little is documented. It could be hypothesized that immune checkpoint inhibitors have possible efficacy, as iris melanoma shows the same UV-induced mutational signatures as cutaneous melanoma [ 48 , 49 ]. As for targeted therapy, it is unknown whether BRAF -mutated iris melanoma responds to BRAF(/MEK) inhibition, as it is not described in the literature.…”

Section: Genetic Biomarkers When Metastatic Disease Is Presentmentioning

confidence: 99%

Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know

Bol

Donia

Heegaard

et al. 2020

IJMS

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Melanoma of the ocular region (ocular melanoma) comprises about 5% of all patients with melanoma and covers posterior uveal melanoma, iris melanoma, and conjunctival melanoma. The risk of metastasis is much higher in patients with ocular melanoma compared to a primary melanoma of the skin. The subtypes of ocular melanoma have distinct genetic features, which should be taken into consideration when making clinical decisions. Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas. In this review, we discuss the genetic biomarkers of the subtypes of ocular melanoma and their impacts on the clinical care of these patients.

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Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Cited by 96 publications

References 58 publications

Insufficient Sun Exposure Has Become a Real Public Health Problem

Insufficient Sun Exposure Has Become a Real Public Health Problem

Iris Colour and the Risk of Developing Uveal Melanoma

Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know

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