Melanocortin-1 receptor (MC1R) and its variants have a pivotal role in melanin synthesis. However, MC1R has been associated to non-pigmentary pathways related to DNA-repair activities and inflammation. The aim of this review is to provide an up-to-date overview about the role of MC1R in the skin. Specifically, after summarizing the current knowledge about MC1R structure and polymorphisms, we report data concerning the correlation between MC1R, phenotypic traits, skin aging, other diseases and skin cancers and their risk assessment through genetic testing.

Germline variants of the melanocortin-1-receptor (MC1R) gene are the most common genetic trait predisposing to cutaneous melanoma (CM). Here, we performed a literature review and meta-analysis of the association between MC1R gene variants and the frequency of somatic mutations of the BRAF, NRAS, and TERT genes in CM patients. We included studies published until January 2020 in MEDLINE, EMBASE, Ovid Medline, and two grey literature databases. Random effect models were used to pool study-specific estimates into summary odds ratio (SOR) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and assess the robustness of pooled estimates. Twelve studies published between 2006 and 2018 (encompassing 3566 CM, mostly on nonacral sites) were included. MC1R gene variants were not significantly associated with the frequency of somatic mutations of the BRAF and NRAS genes. Only three studies focused on somatic mutations of the TERT gene promoter, all of which reported moderate-to-strong positive associations with MC1R germline variants. MC1R gene variants appear to make only moderate changes, if any, to the risk of BRAF- or NRAS-mutant CM. The association with TERT promoter mutations is suggestive, yet it warrants confirmation as it is based on a still limited number of studies.

Afamelanotide (SCENESSE(®)) is a synthetic α-melanocyte stimulating hormone analogue and first-in-class melanocortin-1 receptor agonist that is approved in the EU for the prevention of phototoxicity in adults with erythropoietic protoporphyria (EPP). It is administered subcutaneously as a biodegradable, controlled-release implant containing 16 mg of afamelanotide. This article reviews the clinical efficacy and tolerability of afamelanotide in EPP and summarizes its pharmacological properties. In the phase III trial, CUV039, afamelanotide treatment improved light tolerance in patients with EPP. Compared with placebo, afamelanotide treatment enabled patients to spend more time in direct sunlight without pain and increased the time to the appearance of the first symptoms of phototoxicity provoked by a standardized light source. Afamelanotide was generally well tolerated in this trial, with no drug-related serious adverse events reported. Commonly occurring adverse reactions included headache and implant-site reactions. Efficacy and safety data from earlier phase III trials are consistent with those from the CUV039 trial. Afamelanotide, approved in the EU for the prevention of EPP phototoxicity, represents a useful addition to the management of the disorder.

Since the identification of S100 protein as an immunohistochemical marker that could be useful in the diagnosis of melanoma in the early 1980s, a large number of other melanocytic-associated markers that could potentially be used to assist in the differential diagnosis of these tumors have also been investigated. A great variation exists, however, among these markers, not only in their expression in some subtypes of melanoma, particularly desmoplastic melanoma, but also in their specificity because some of them can also be expressed in nonmelanocytic neoplasms, including various types of soft tissue tumors and carcinomas. This article reviews the information that is currently available on the practical value of some of the markers that have more often been recommended for assisting in the diagnosis of melanomas, including those that have only recently become available.

Skin pigmentation is one of the most overt human physical traits with consequences on susceptibility to skin cancer. The variations in skin pigmentation are dependent on geographic location and population ethnicity. Skin colouration is mainly due to the pigmentation substance melanin, produced in specialized organelles (melanosomes) within dendritic melanocytes, and transferred to neighbouring keratinocytes. The two types of melanin synthesized in well defined chemical reactions are the protective dark coloured eumelanin and the sulphur containing light red-yellow pheomelanin. The events leading to the synthesis of melanin are controlled by signalling cascades that involve a host of genes encoding ligands, receptors, transcription factors, channel transporters and many other crucial molecules. Several variants within the genes involved in pigmentation have been associated with high risk phenotypes like fair skin, brown-red hair and green-blue eyes. Many of those variants have also been implicated in the risk of various skin cancers. The variants within the key pigmentation gene, melanocortin-receptor 1 (MC1R), in particular have been ubiquitously linked with high risk traits and skin cancers involving both pigmentary and non-pigmentary functions and likely interaction with variants in other genes. Many of the variants in other genes, functional in pigmentation pathway, have also been associated with phenotypic variation and risk of skin cancers. Those genes include agouti signalling protein (ASIP), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), oculocutaneous albinism II (OCA2), various solute carrier genes and transporters. Most of those associations have been confirmed in genome wide association studies that at the same time have also identified new loci involved in phenotypic variation and skin cancer risk. In conclusion, the genetic variants within the genes involved in skin pigmentation besides influencing phenotypic traits are important determinants of risk of several skin cancers. However, ultimate risk of skin cancer is dependent on interplay between genetic and host factors.

Tremendous progress has been made in identifying genes involved in pigmentation in dogs in the past few years. Comparative genomics has both aided and benefited from these findings. Seven genes that cause specific coat colours and/or patterns in dogs have been identified: melanocortin 1 receptor, tyrosinase related protein 1, agouti signal peptide, melanophilin, SILV (formerly PMEL17), microphthalmia-associated transcription factor and beta-defensin 103. Although not all alleles have been yet identified at each locus, DNA tests are available for many. The identification of these alleles has provided information on interactions in this complex set of genes involved in both pigmentation and neurological development. The review also discusses pleiotropic effects of some coat colour genes as they relate to disease. The alleles found in various breeds have shed light on some potential breed development histories and phylogenetic relationships. The information is of value to dog breeders who have selected for and against specific colours since breed standards and dog showing began in the late 1800s. Because coat colour is such a visible trait, this information will also be a valuable teaching resource.

OBJECTIVE: The clinical phenotypes of familial melanoma syndromes and genetic and environmental interactions are reviewed to summarize the current status of the field and to identify gaps in molecular and clinical investigations.
RESULTS: The familial melanoma syndromes are associated with germline mutations in three highly penetrant gene products: p16, alternate reading frame, and cyclin-dependent kinase 4. Certain variants in a low-penetrance gene, MC1R, the melanocortin 1 receptor gene, increase melanoma risk to a lesser extent and act as a genetic modifier when cosegregating with a deleterious p16 gene. The penetrance of these melanoma-predisposing genes is largely influenced by ultraviolet exposure across geographic latitude. Yet cumulative studies are conflicting on whether ultraviolet radiation, including sunburns, early childhood and adolescent sun exposure, and chronic exposure, increases melanoma risk in familial melanoma. To date, the clinical phenotypes of increased number of atypical nevi and nevi body distribution are independent risk factors for melanoma risk, regardless of family history. The atypical mole syndrome cannot reliably predict melanoma germline mutations but increases melanoma risk in p16 mutation carriers. Familial melanoma patients develop melanomas earlier and are prone to developing multiple primary melanomas. Other than these two differences, familial and sporadic melanoma share similar histopathology, prognostic factors, and survival rates.
CONCLUSIONS: Familial melanoma is an excellent human model system for the investigation of melanoma. Understanding genotype-phenotype and environmental relationships in familial melanoma will likely lead to improved understanding of pathogenesis for all melanoma patients.