Human Determinants and the Role of Melanocortin-1 Receptor Variants in Melanoma Risk Independent of UV Radiation Exposure

Abstract

IMPORTANCE Despite the unquestioned relationship of UV radiation (UVR) exposure and melanoma development, UVR-independent development of melanoma has only recently been described in mice. These findings in mice highlight the importance of the genetic background of the host and could be relevant for preventive measures in humans. OBJECTIVE To study the role of the melanocortin-1 receptor (MC1R) and melanoma risk independently from UVR in a clinical setting. DESIGN, SETTING, AND PARTICIPANTS Hospital-based case-control study, including genetic testing, questionnaires, and physical data (Molecular Markers of Melanoma Study data set) including 991 melanoma patients (cases) and 800 controls. MAIN OUTCOMES AND MEASURES Association of MC1R variants and melanoma risk independent from sun exposure variables. RESULTS The 1791 participants included 991 with a diagnosis of melanoma and 800 control patients (mean [SD] age, 59.2 [15.6] years; 50.5% male). Compared with wild-type carriers, carriers of MC1R variants were at higher melanoma risk after statistically adjusting for previous UVR exposure (represented by prior sunburns and signs of actinic skin damage identified by dermatologists), age, and sex compared with wild-type carriers (Ն2 variants, OR, 2.13 [95% CI, 1.66-2.75], P < .001; P for trend <.001). After adjustment for sex, age, sunburns in the past, and signs of actinic skin damage, the associations remained significant (OR, 1.65 [95% CI, 1.

Immune and molecular correlates in melanoma treated with immune checkpoint blockade

“…In addition to the lack of dark UV-shielding eumelanin, these individuals have an increased risk of melanoma independent of UV exposure thought to be related to pro-oxidant roles of red/blond pheomelanin pigment 66 , and their melanomas have higher numbers of both UV and non-UV associated mutational loads 67 . The finding of UV-independent melanoma risk among MC1R-variants (redheads) has been recently corroborated in humans 68 .…”

A Phase II Randomized Placebo-Controlled Trial of OralN-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative StressIn Vivo

“…There is a good deal of correlative evidence suggesting that one link between UV radiation and melanoma may lie in the generation of oxidative damage (14), and melanoma has been referred to as a “reactive oxygen-driven tumor” (15). Germline variants in the melanocortin-1 receptor (MC1R), which regulates UV-induced ROS production and metabolism in melanocytes (16), are relatively common, and several are associated with melanoma predisposition independent of UV exposure (17). Finally, we reported that the antioxidant N -acetylcysteine (NAC) can delay tumor development in an animal model of UV-induced melanoma (18).…”

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“…Moreover, in the absence of UVR exposure, regardless of their epidermal melanocyte status ( ± ), black and albino C57BL/6 mice on a mutated BRAF V600E background developed similarly low rates of CMM after a long latency period, whereas over half the mice with red hair developed melanomas after only a year 69 . Recently, scientists confirmed the human variants of the MC1R red hair gene dramatically increase the risk for getting CMM independent of UVR exposure 70 . Furthermore, both homozygote and heterozygote red hair melanocortin-1-receptor variants are sensitive to UVR exposure 71 and have eumelanin to pheomelanin ratios of only 1.46 and 4.44, respectively, while wild types have 5.81 (p < 0.001) 72 .…”