Variants of the melanocortin-1 receptor: do they matter clinically?
2014
Abstract
The melanocortin 1 receptor (MC1R) gene encodes for a seven-pass transmembrane receptor primarily expressed on melanocytes and melanoma cells. Single nucleotide polymorphisms (SNPs, also termed variants) in MC1R frequently cause red hair, fair skin and are associated with melanoma and keratinocyte-derived skin cancer development. Activation of wild-type (WT) MC1R in skin assists cutaneous photo-protection whereas reduced MC1R signalling, seen with MC1R variants, impairs ultraviolet radiation (UVR)-protective responses. As ancestral humans migrated out of Africa, the evolutionary advantage of MC1R variants may have related to improved cutaneous vitamin D synthesis and higher birth-weight reported with certain MC1R variants. Reduced photoprotection secondary to MC1R dysfunction involves pigmentary and non-pigmentary mechanisms (reduced DNA repair, effects on cell proliferation and possibly immunological parameters), leading to clonal expansion of mutated cells within skin and subsequent carcinogenesis. Recent investigations suggest an association between MC1R genotype and vitiligo, with preliminary evidence that a MC1R agonist, [Nle4-D-Phe7]-alpha-MSH, in combination with UVB, assists repigmentation. Future development of compounds to correct defective MC1R responses secondary to MC1R variants could result in photoprotective benefits for fair-skinned individuals and reduce their skin cancer risk.
Introduction
In 1857, William Norris noted that people with multiple moles were prone to developing ‘melanosis’ (melanoma) and that affected individuals had ‘fair complexions’. Although we are now well aware of the association between fair skin and increased skin cancer risk, and the causal association between melanocortin 1 receptor (MC1R) gene variants (especially Arg151Cys, Arg160Trp and Asp294His) and fair skin, an important question is whether MC1R variants matter from a clinical perspective.
The melanocortin 1 receptor (MC1R)
The complex process of melanin production in melanosomes within melanocytes is influenced by numerous factors, one of which is MC1R. Variation in skin and hair color in humans is governed by the extent of eumelanin and phaeomelanin in these tissues, with dark-haired and dark-skinned individuals having abundant eumelanin and people with red hair and pale skin having less eumelanin and an altered phaeomelanin] can direct signalling via cyclic AMP, extracellular signal-regulated kinases ERK1 and ERK2, and through MC1R's interaction with phosphatase and tensin homologue (PTEN).
MC1R variants may impact differently on intra-cellular signalling pathways downstream of MC1R (e.g. Arg151Cys, Arg160Trp and Asp294His variants hinder cAMP more than ERK signalling), and from their role in red hair/fair skin, MC1R variants arguably cause one of the more dramatic changes in normal human pigmentation. Indeed, when MC1R signalling is dysfunctional or inactive, melanin production defaults towards lower total melanin in skin and phaeomelanogenesis in hair. Evidence for this comes from associations of non-functional MC1R variants which compromise cAMP signalling with lower cutaneous melanin levels in Mc1r-null than MC1R-transgenic pigmented hairless mice, and higher phaeomelanin]
There are a number of intra-cellular signalling pathways (primarily initiated from cell surface receptors) which are involved in promoting pigmentation in humans. In addition, some of these intra-cellular factors, for example cAMP, can be produced as a result of other mechanisms and may influence the ultimate pigmentary phenotype of subjects. However, the clinical/phenotypic effects of reduced pigmentation and increased skin cancer susceptibility in people with variant MC1R indicate that MC1R is one of the key players in this process.
Evolutionary advantage of MC1R variants
Consistent with eumelanin being photoprotective in human skin in vivo, MC1R variant individuals are less protected against UVR. While this has relevance to skin cancer development, another important consideration is whether MC1R variants offer evolutionary advantages, that is why did MC1R variants become prevalent in white-skinned populations?
In animals such as mice, effects of Mc1r alterations on coat color offer advantages through environmental camouflage. In humans, a lack of cutaneous melanin in our African hunter-gatherer ancestors would have led to blistering sunburn and subsequent infection, resulting in reduced survival, especially as many African countries experience high levels of solar radiation. Protection against sunburn as a reason for darker skin in Africa has been questioned, but severe sunburn can indeed be life-threatening and breaks in skin can allow entry of infectious agents causing systemic sepsis. Additionally, melanin may protect against folate degradation, therefore reduced skin melanin in our hunter-gatherer ancestors might have caused folate deficiency with consequent neural tube birth defects such as spina bifida thereby limiting offspring survival.
Following our ancestors’ migrations ‘out of Africa’, debate exists over whether MC1R variants arose in European populations secondary to less functional constraint (because photoprotection was less necessary) or due to an ‘active drive’ to reduce photoprotection. The advantage of lower skin melanin content from MC1R variants during these migrations includes UVR-induced cutaneous vitamin D synthesis in societies with predominantly cereal-based diets (lacking in fat-soluble vitamins); women deficient in vitamin D can suffer from pelvic deformity thereby complicating childbirth (hence reducing the chance of contributing to the next generation's gene pool). Additionally, certain MC1R variants are associated with higher birth weight, and as low birth weight can lead to reduced survival, MC1R variants may have offered significant evolutionary advantages especially when food was less plentiful. Sexual selection, a hypothesis which Charles Darwin favored, may also have influenced the spreading of fair skin/MC1R variants amongst populations.
Photoprotection and skin cancer
Numerous processes affect skin cancer development (including alterations in CDKN2A, CDK4, TP53, BRAF, PTCH and nucleotide excision repair genes, immunosuppression and carcinogen exposure); however, reduced pigmentation is a significant risk factor for UVR-induced skin carcinogenesis in people exposed to UVR. The higher frequency of skin cancer in MC1R variant subjects highlights the importance of understanding MC1R biology and SNPs within MC1R in the clinical arena. Germline MC1R variants are associated with melanoma and keratinocyte-derived skin cancer, with most studies indicating these associations remain after controlling for skin type/hair color. Additionally, MC1R genotype may be a better predictor of early-onset melanoma than pigmentation status, perhaps in part due to limitations in phenotyping human pigmentation characteristics, but non-pigmentary mechanisms might also promote skin cancer development in MC1R variant individuals. Admittedly, elucidation of these processes is subject to caveats of extrapolation to humans from in vitro and in vivo models, because rodent skin differs from human skin, and mice, being nocturnal, are normally relatively UVR-spared. Although melanin, especially eumelanin, protects against UVR, MC1R's role in photoprotection goes beyond simply promoting eumelanogenesis. For example, alpha-MSH (which, similar to MC1R, increases following UVR exposure) promotes nucleotide excision repair in melanocytes and keratinocytes. However, MC1R variants reduce capacity for DNA repair in vitro, and probably, in vivo because albino hairless Mc1r-null mice develop more p53-mutated keratinocyte epidermal patches following repeated UVR exposure than albino mice with WT MC1R. The in vivo study showed no significant difference in the amount of cyclobutane pyrimidine dimers between WT MC1R and Mc1r-null mice, and a more recent study comparing WT Mc1r and Mc1r-null mice confirmed this observation, thus greater numbers of p53 patches would be consistent with diminished repair of UVR-induced DNA damage and increased proliferation of mutated keratinocytes. Furthermore, transcriptional profiling of neonatal skin from WT and Mc1r-null mice indicates that Mc1r-dependent UVB responses involve altered transcription of multiple genes regulating cell cycle, suggesting that continued cell division in epidermal cells which have not adequately repaired their DNA damage contributes to skin carcinogenesis in MC1R variant individuals. Another pro-tumorigenic factor may be the higher UVR-induced reactive oxygen species (ROS) production in variant MC1R than in WT MC1R cells, perhaps via Nrf2 and p53 signalling. MC1R regulates UVR-induced ROS production in WT but not Arg151Cys MC1R-transfected HaCaT keratinocytes and recent data in fibroblasts indicate that loss of function MC1R variants also confers lower protection against UVR-induced ROS. Another potential MC1R-mediated photoprotective mechanism is UVR-induced epidermal thickening. Moreover, consistent with MC1R's role in photoprotection, MC1R variants are associated with increased photo-aging.
Reduced photoprotection by MC1R variants affects skin cancer development in vivo, but other mechanisms could also be involved. Interactions between PTEN and WT MC1R, but not variant MC1R, may be relevant to melanomagenesis, especially in BRAF-mutated cells. In addition, alpha-MSH (released in an MC1R-related manner from melanoma cells and by necrotic melanoma cells) can suppress proliferation and alter extracellular matrix binding of melanoma cells containing WT MC1R but not those expressing variant MC1R. MC1R is also expressed on other cell types, including immune cells, and alpha-MSH can exert immunosuppressive effects through MC1R (and MC3R to some extent). Indeed, Loser et al. demonstrated that alpha-MSH/MC1R signalling induced cytotoxicity by tumor antigen-specific CD8+ T cells, consequently reducing B16-OVA melanoma growth in WT Mc1r but not Mc1r-null mice; therefore, it is possible that reduced anti-melanoma T-cell cytotoxicity in MC1R variant individuals might permit unrestricted tumor growth. Notwithstanding, variant MC1R patients with melanoma may actually have a better prognosis than those with WT MC1R, and other studies have not detected any relation between MC1R genotype and lymphocyte function. Furthermore, some authors consider MC1R dispensable in regulating immune responses in animal models.
In 1857, William Norris noted that patients with melanoma had multiple moles and/or were fair-skinned. Although genome-wide association studies (GWAS) have not documented any association between MC1R variants, and number of melanocytic naevi, fewer acquired melanocytic naevi have been noted in red-haired individuals and MC1R variant subjects. Moreover, red hair/fair skin/MC1R variants may have an association with ‘white’ dysplastic melanocytic naevi (and amelanotic melanoma). Similarly, in patients with multiple melanomas, benign melanocytic naevi of MC1R variant carriers were significantly more likely to exhibit atypia on dermoscopy and plump bright cells in the upper dermis on confocal microscopy. In the same study, when MC1R variants were combined with the G101W CDNK2A missense mutation, the naevi were more likely to be hypopigmented and contain dermoscopically visible vessels. Furthermore, a larger study highlighted that MC1R variants in CDNK2A mutation carriers modify the dermoscopic pattern, with ‘structureless areas’ more frequent in individuals with two MC1R variants. In conjunction with the association between MC1R variants and congenital melanocytic naevi, these studies suggest that MC1R variants can influence development of melanocytic naevi. However, it is unclear whether the effect on numbers of acquired melanocytic naevi is simply due to reduced pigmentation rendering naevi less visible in fair-skinned subjects.
The results of kindred investigations and GWAS on melanoma indicate numerous melanoma susceptibility loci exist. Unsurprisingly, MC1R genotype would be expected to alter melanoma risk due to other susceptibility genes, and in kindreds affected by CDKN2A germline mutations, MC1R variants are an important influence on who develops melanoma in these families (although it should be noted that one study showed variant MC1R modifies melanoma risk in CDKN2A-negative rather than CDKN2A-positive individuals). Exome sequencing has shown an abundance of somatic genetic events in melanoma, and again it would be expected that the activity/degree of melanocyte MC1R signalling might directly or indirectly influence how somatic mutations affect early melanomagenesis. Related to this, an association between germline MC1R genotype and the commonly encountered BRAF mutation in certain types and/or sites of cutaneous melanoma has been suggested, but some other studies did not observe this association and it is unclear whether these varied results relate to the functional impact of various MC1R SNPs or an effect by some hitherto unrecognized gene/protein product which might influence this interaction. Although BRAF-mutated Mc1r-null mice can develop cutaneous melanoma without UVR exposure, the relevance to humans is unclear because the scalp in women and the buttocks of both sexes (i.e. non-sun exposed sites) are the least common skin sites for melanoma, indicating that spontaneous development of melanoma in the absence of UVR is infrequent in human skin.
Hypopigmentary disorders
Széll et al. suggested a role for the Arg160Trp MC1R variant in protecting against vitiligo, and a recent GWAS documented an association between the MC1R locus and generalized vitiligo, although causality of this association remains undetermined. The mechanisms whereby different MC1R variants may protect against or lead to vitiligo are uncertain and various theoretical possibilities exist. For example, it is unclear whether certain variant receptors display reduced antigenicity or are altered by UVR-induced ROS to serve as autoantigens, influence cytotoxic T cell or other anti-melanocyte immune responses, alter oxidative stress within melanocytes, or affect migration of melanocytes from melanocyte stem cell compartments. In relation to the latter, upon UVB exposure melanocyte stem cells migrate in a Mc1r-dependent manner from murine hair follicles and differentiate into epidermal melanocytes to protect the epidermis. This migration from the follicular niche occurs before cell division, raising concerns that it might deplete the melanocyte stem cell pool. It is conceivable that MC1R variants might affect melanocyte stem cell migration following traumatic stimuli/koebnerisation, thus cells could fail to leave the stem cell compartment to replenish the epidermis, leading to vitiligo. Indeed, a small study using the MC1R agonist, [Nle4-D-Phe7]-alpha-MSH, in combination with narrow-band UVB has shown promising results in four patients with generalized vitiligo with poor treatment responses to narrow-band UVB alone, suggesting pharmacologically modulating MC1R-dependent migration of melanocyte stem cells from the follicle is possible. A theoretical impact of MC1R variants on migration from the follicular melanocyte stem cell pool could also be hypothesised in causing idiopathic guttate hypomelanosis (white spots), which predominantly affects fair-skinned individuals and is characterized by well-circumscribed white macules on sun-exposed sites which, according to some studies, contain decreased epidermal melanocytes.
Conclusions
While obvious benefits exist for MC1R forensic genotyping at relevant crime scenes (two MC1R variant alleles suggest higher likelihood of red hair), the advantages of MC1R genotyping in the clinical setting are not so straightforward. Despite this, it is important for clinicians to understand MC1R biology and how MC1R variants increase skin cancer risk, particularly when answering questions by fair-skinned subjects such as ‘why did I get skin cancer when my partner/relative/friend, who has received as much sun exposure as me, has not been affected?’ At present, MC1R genotyping arguably offers little over phenotyping; however, as additional information on MC1R becomes available, MC1R genotype may tell clinicians more in terms of skin cancer risk than pigmentation status alone, and so may form part of a future multigene assay of risk. That MC1R variants promote skin cancer development through pigmentary and non-pigmentary mechanisms suggests pharmacologically targeting MC1R signalling to augment photoprotection in MC1R variant subjects and lower skin cancer risk may be possible in future years. In support of this, Barnetson et al. demonstrated [Nle4-D-Phe7]-alpha-MSH increased pigmentation and decreased UVR damage in fair-skinned individuals (likely to have MC1R variants but were not actually genotyped). Similarly, D'Orazio et al. showed forskolin (which activates adenylyl cyclase, increasing intra-cellular cAMP and thus circumventing faulty MC1R) protected Mc1r-null mice against UVR. However, synthetic alpha-MSH peptides have been associated with eruption of atypical melanocytic naevi, and forskolin would not be suitable for use in humans. Unfortunately it may be challenging to encourage the pharmaceutical industry to engage in trials investigating the ability of suitable agents which correct variant MC1R signalling to prevent skin cancer development.
Only think that* this article do not mention , is that not only UV radiation causes Melanoma. There are more unknow causes that we still doesn´t get to know.
there are many different chemicals that are thought to cause melanoma(just read hasmat warnings on different ones), also radiation can play a part in it , but the most common by far is UV, it would be over 99% caused by UV. so the main research is on UV .
There is some cases of melanoma, including bucal and intestinal melanoma, that is not triggered by the UV radiation ,* also in places whithout UV radiation , where the sun has never touch.
mayo states that this is rare. but often invasive melanoma travels to other places, and as I stated there are other things that can cause it but again they are rare.
I am interested in this, but I feel like this is such a rare occurrence. Melanoma can be a part of a bigger problem and caused by different things rather than just peptides/
1. UV light
2. Moles
3. Birthmarks
4. Skin colour and Freckles
5. Sunburn
6. Place of Birth
7. Sunbeds
8. Family History
9. Other medical conditions which put you at higher risk for melanoma (Parkinson's disease, previous cancer, inflammatory bowel diseases)
Hormones are not yet proven to be causing melanoma. Though melanotan is believed by some to increase moles or darken it, the idea that it causes melanoma is still not proven. There are many factors affecting the occurrence of melanoma and you would have to rule them out before deciding on melanotan use as the culprit.
We should all be careful with moles. I knew someone who realized she had cancer when it was already too late. It started with a small mole under her fingernails.
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