Iris Colour and the Risk of Developing Uveal Melanoma

Abstract

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.

The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma

“…The quality and quantity of melanin determines the extent of susceptibility to UVR damage in melanocytes and this correlates with UM risk. Having light (blue, gray, green or hazel) coloured eyes as opposed to dark (brown or black) coloured eyes has frequently been found to be a mild to major risk factor for developing UM (see Table 1 ) in Australia [ 33 , 34 ] and countries in the northern hemisphere [ 30 , 32 , 35 ]. This could be due to the UVR protective properties of eumelanin in darker eye colours [ 5 ].…”

“…This was repeated in a study investigating 16 European countries (6673 patients from 1983 to 1994), where incidence rates increased, rather than decreased, with latitudes further away from the equator [ 25 ]. This could be attributed to a higher proportion of light-coloured eyes in northern Europe [ 25 , 35 ]. However, an analysis of 2142 ocular melanomas from 1992–2002 in the US, which focused on non-Hispanic whites, revealed a significant increase (4.91- fold) in UM incidence with increasing latitudes (20–22° to 47–48°) [ 94 ].…”

Validation of the Relationship Between Iris Color and Uveal Melanoma Using Artificial Intelligence With Multiple Paths in a Large Chinese Population

“…Although several studies from Canada, the United States, Germany, France, the Netherlands, and Australia have shown that UM is more prevalent in people with lighter iris color ( Gallagher et al, 1985 ; Holly et al, 1990 ; Seddon et al, 1990 ; Pane and Hirst, 2000 ; Guénel et al, 2001 ; Stang et al, 2003 ; Schmidt-Pokrzywniak et al, 2009 ; Houtzagers et al, 2020 ), the proportion of patients with brown eyes in these studies is very low. Therefore, the relationship between iris color and the incidence of UM in the Asian population requires a closer examination.…”

“…Lack of pigmentation leads to more light penetration into the uvea and less protection from ultraviolet radiation (UV), which increases the risk of UM ( Egan et al, 1988 ; Singh and Topham, 2003 ). It has also been suggested ( Houtzagers et al, 2020 ) that most UV rays are absorbed by the cornea, lens, and vitreous, while other wavelengths, such as visible light, penetrate the back of the eye and contribute to the production of toxic reactive oxygen species (ROS), thereby increasing the chance of malignant transformation of uveal melanocytes.…”

<p>Research Progress of Cancer Stem Cells in Uveal Melanoma</p>

“…The incidence of UM is associated with several individuals’ backgrounds, including race, age, iris color, etc. 1 , 2 For example, it is more prevalent in Caucasians with light irises than brown eyes. The annual incidence in European and American people is approximately 3.75–5.2 cases per million persons, 3 , 4 which is significantly higher than that in Asians and Africans.…”