MC1R Variant Independently Linked With Melanoma


People who are carriers of two variants of MC1R, a gene that regulates pigmentation, were at increased risk for melanoma regardless of previous UV radiation exposure.

People who are carriers of two variants of melanocortin-1 receptor (MC1R), a gene that regulates pigmentation, were at increased risk for melanoma regardless of previous UV radiation exposure, according to the results of a study published in JAMA Dermatology.

Researcher Judith Wendt, MD, PhD, of Medical University of Vienna, Austria, and colleagues, wrote that these results have global relevance “due to the frequency of these variants among the high-risk population.”

In an editorial that accompanied this study, Elisabeth M. Roider, MD, and David E. Fisher, MD, PhD, of Massachusetts General Hospital, wrote: “Overall, this carefully performed study indicates that individuals carrying MC1R variants display a UV-independent significant intrinsic risk, highlighting a need to better understand how MC1R variants, pheomelanin, and ROS affect melanoma development and how to protect these individuals at elevated risk.”

The case-control study included genetic testing, questionnaires and physical data from 1,791 participants; 991 had melanoma and 800 were control patients.

Looking at the whole population, the researchers found a significant association between participants who reported more than 12 sunburns and risk for melanoma (P < .001), as well as increased risk for melanoma among participants who reported 10 or more sunburns during childhood or adolescence (P < .001). In addition, increased melanoma risk was identified among patients who had severe signs of actinic skin damage on the back and neck, face, or hands (P < .001 for all).

The researchers examined melanoma risk associated with several variants of MC1R. After adjusting for age and sex, patients with two or more variants had twice the risk for melanoma compared with wild-type patients (odds ratio [OR], 2.13 [95% CI, 1.66–2.75]; P < .001). Increased risk for melanoma was found for patients with both “R” variants and “r” variants:

R/R: OR, 1.77 [95% CI, 1.12–2.79]
R/r: OR, 2.93 [95% CI, 2.07–4.16]
R/0: OR, 1.94 [95% CI, 1.45–2.60]
r/r: OR, 1.64 [95% CI, 1.13–2.38]
r/0: OR, 1.35 [95% CI, 1.05–1.73]

“As described by others, particularly high-risk variants (R/R, R/r, R/0) were associated with a characteristic pigmentation phenotype such as fair skin type, red hair color, and the presence of freckles in childhood,” the researchers explained.

Next, Wendt and colleagues measured melanoma risk after adjusting for sun exposure variables. An analysis adjusted for facial actinic skin damage and sunburns in childhood and adolescence showed an increased risk for melanoma among patients who were carriers of MC1R variants:

R/R: OR, 1.65 (95% CI, 1.02–2.67)
R/r: OR, 2.63 (95% CI, 1.82–3.81)
R/0: OR, 1.83 (95% CI, 1.36–2.48)
r/r: OR, 1.50 (95% CI, 1.01–2.21)

Similar levels of increased risk were found when the analysis adjusted for dorsal actinic skin damage plus sunburns in childhood and adolescence.

“The study by Wendt and colleagues provides valuable insight into a silent UV-independent melanoma risk that has no clear current preventive strategy,” editorialists Roider and Fisher wrote. “For now, lightly pigmented individuals need to understand the risks associated with sun exposure and should use physical sun protection whenever possible. Regular skin examination and thorough self-examination remain valuable steps toward halting melanoma mortality.”

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