Melanocortin-1 receptor: Loss of function mutations and skin cancer
Christina D Mumm, Michelle Draznin MD
Dermatology Online Journal 12 (5): 13

Abstract

We present a red-haired patient who came to our clinic seeking information regarding his predisposition to skin cancer. We discuss the receptor involved in hair color and the allelic variants that lead to red hair. These variants are often characterized by loss of function mutations, which lead to a predisposition to non-melanoma skin cancers, with relative risks reaching as high as a 6.7 in one study. Most concerning, however, is that some of these loss of function mutations may act synergistically with genetic mutations that cause familial melanomas. Thus, red haired patients with familial melanoma syndromes have a greater risk of melanoma than those patients with familial melanoma syndromes alone.

Clinical synopses

Case Scenario 1

A 31-year-old man with red hair and fair skin presents to the clinic for an enlarging lesion on his abdomen. The patient reports repeated sun exposure as an adolescent. Examination reveals a 3 × 3mm new, slowly growing papule with overlying telangiectasias. A biopsy is performed and histopathological examination shows a basal cell carcinoma. Islands of basophilic cells are seen in palisading arrangements. There is a gray appearing mucinous stroma surrounding one of these islands. The host response is evident by the presence of lymphocytes (Figs. 1 and 2). The lesion is excised and no further testing is done.

Figure 1	Figure 2
Islands of basophilic cells are seen in palisading arrangements. There is a gray appearing mucinous stroma surrounding one of these islands. The host response is evident by the presence of lymphocytes. Hematoxylin and eosin stain; Mag: 10X.

Comment

Red is the longest visible wavelength of light and it is the color with the least amount of scatter; in terms of hair, the color red is quite distinctive. For many adults, it is a desirable hair color, but for children, it is often a source of embarrassment because they may be called "carrot-top" and other unpleasant names. It has been estimated that 2-5 percent of people in the United States have naturally red hair. Many myths throughout time have been related to red hair. For example, ancient Romans considered redheads to be unlucky but the ancient Egyptians considered redheads to be closely associated with the gods. In fact, several of the Egyptian pharaohs are described as being redheads. Examples of famous redheads include Queen Elizabeth I of England, Napoleon Bonaparte, Winston Churchill, Galileo, Vincent van Gogh, Ulysses S. Grant, Thomas Jefferson, William Shakespeare, Mark Twain and George Washington. Dermatology is concerned with red-haired individuals since they have increased photosensitivity and produce skin cancers at an increased rate compared to their non-redheaded counterparts [1, 2].

The pigmentation of hair and skin is due to melanin produced in the cytoplasm of the hair follicle melanocytes [3]. Melanin exists in two forms in human skin and hair: eumelanin, which is a brown-black color and pheomelanin, which is a yellow-red color. Black hair contains mostly eumelanin with very dense melanosomes. These melanosomes become less dense as the hair color lightens. Red hair is the result of an increased ratio of pheomelanin to eumelanin, together with melanin that is scantly deposited on the matrix fibers [4]. Blond hair contains decreased amounts of both types of melanin. The ratio of skin eumelanin to pheomelanin is higher in individuals with Fitzpatrick skin types V and VI as compared to types I and II [5]. Eumelanin and pheomelanin are also involved in the photoprotection and cytotoxic properties of skin. Eumelanin confers photoprotection as a result of eumelanosomes forming supranuclear melanin caps that protect the nuclei of the melanocytes and keratinocytes from ultra-violet radiation. Pheomelanin is photolabile, with free radical production following ultra-violet light exposure, which results in photosensitivity [6].

The melanocyte stimulating hormone receptor involved in hair color is the melanocortin-1 receptor (MC1R) on chromosome 16. The MC1R gene is highly polymorphic and several allelic variants have been associated with red hair. Currently, up to 65 alleles of the MC1R gene have been described with at least 9 having an association with red hair [7]. The MC1R is a G-protein coupled receptor with 317 amino acids and seven transmembrane segments. The ligands for the MC1R are α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone. When the MC1R is stimulated with α-MSH, cyclic-AMP levels increase which leads to an increase in protein kinase A. The increase in protein kinase A leads to an increase in the transcription of microphthalmia transcription factor. Once microphthalmia transcription factor is activated, an increase in tyrosinase occurs, which is the rate-limiting step of melanin synthesis. Tyrosinase activation causes an increase in eumelanin synthesis and melanocyte proliferation. Loss of function variants in MC1R can lead to a decrease in cyclic-AMP, which ultimately leads to a decrease in eumelanin, an increase in pheomelanin and the red-hair, fair-skin phenotype [8]. Additionally, α-MSH via the MC1R has been shown to have a positive effect on the differentiation of melanocytes [9] and can exhibit immunomodulatory and anti-inflammatory effects [10]. Therefore, individuals with loss of function of MC1R may be at increased risk for skin cancer due to lack of eumelanin, lack of differentiation of melanocytes and loss of the inherent defense mechanisms of melanocytes and keratinocytes.

The loss of function mutations most commonly described in the literature as associated with red hair are Asp84Glu, Arg142His, Arg151Cys, Arg160Trp and Asp294His [11]. These more common mutations and others associated with red hair appear to have varying degrees of loss of function effects on the MC1R. The five mutations mentioned above also appear to have a high penetrance. It is estimated that approximately 80 percent of red-haired individuals have significant changes in both MC1R genes [12]. Flanagan et al. also found that a single MC1R allele change can produce a phenotype with the inability to tan, and a change in both MC1R alleles results in the red-hair, fair-skin phenotype.

Matichard et al. [13] studied a population in France and found that MC1R mutations conferred a significant risk for developing melanoma (odds ratios of 4.3 for one variant allele and 6.78 for two variant alleles). Kennedy et al. described the odds ratios for developing melanoma after adjusting for skin type as 3.6 (95% CI 1.7-7.2) for two variant mutations and 2.7 (95% CI 1.5-5.1) for one variant mutation [14]. The presence of the variant Asp84Glu imposed the highest risk for cutaneous melanoma with odds ratios of 16.1 (95% CI 2.3-139.0) for homozygotes and 8.1 (95% CI 1.2-55.9) for heterozygotes. In addition to MC1R loss of function alleles conferring risk for melanoma, these alleles have also been shown to increase the risk for basal cell and squamous cell carcinomas with an odds ratio of 3.15 (95% CI) specifically for the Arg151Cys, Arg160Trp, and Asp294His alleles [15].

The development of skin cancer, particularly melanoma, is a multi-factorial process that includes skin type, genetics and sun exposure. As previously discussed, the MC1R loss of function variants have been shown to have effects on skin type and the response to sun exposure. Additionally, the MC1Rhas been postulated to have non-pigmentary effects that can also lead to the development of melanoma in people with loss of function of this receptor [16]. It has been suggested that α-MSH can produce an inhibitory effect on MC1R to help prevent the growth of melanoma. In individuals with loss of function mutations of the MC1R, this inhibitory effect is lacking and the melanoma grows unopposed.

Additionally, the MC1R loss of function alleles appear to act synergistically with familial genetic variants that have already been shown to cause melanomas. Mutations of the cyclin-dependent kinase inhibitor gene, cyclin-dependent kinase 2A (CDKN2A), has been shown to dramatically increase melanoma cases within certain pedigrees [17]. An investigation of two modifying factors for melanoma risk, CDKN2A and MC1R variants, showed that the presence of an MC1R variant in addition to a CDKN2A mutation significantly increased the raw melanoma penetrance and decreased the age at onset by up to 20 years compared with individuals with only the CDKN2A mutation [18]. This study found that the presence of homozygous MC1R variant alleles increased melanoma penetrance from 50 to 84 percent in individuals with the CDKN2A mutation. The mean age of melanoma onset was decreased from 58 years to 37.8 years. At 50 years of age, 81 percent of individuals with both a CDKN2A mutation and an MC1R variant had developed melanoma, whereas only 57 percent of those carrying a CDKN2A mutation alone had developed melanoma. The presence of an MC1R variant alone was estimated to account for 14 percent risk of developing melanoma by age 50 years.

Although red hair is an exotic characteristic, it often serves as a marker for individuals who are at increased risk for melanoma, squamous cell carcinoma, and basal cell carcinoma. Patients with red hair should be warned of this risk and advised to be prudent about sun exposure. We do not advise our patients to undergo MC1R phenotyping since at this point; knowledge of the exact variant provides no clinical insight.

References

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