Gene Summary

Gene:MC1R; melanocortin 1 receptor
Aliases: CMM5, MSH-R, SHEP2
Summary:This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:melanocyte-stimulating hormone receptor
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MC1R (cancer-related)

Johansen P, Andersen JD, Madsen LN, et al.
Pigmentary Markers in Danes--Associations with Quantitative Skin Colour, Nevi Count, Familial Atypical Multiple-Mole, and Melanoma Syndrome.
PLoS One. 2016; 11(3):e0150381 [PubMed] Free Access to Full Article Related Publications
To investigate whether pigmentation genes involved in the melanogenic pathway (melanogenesis) contributed to melanoma predisposition, we compared pigmentary genetics with quantitative skin pigmentation measurements, the number of atypical nevi, the total nevus count, and the familial atypical multiple mole and melanoma (FAMMM) syndrome. We typed 32 pigmentary SNP markers and sequenced MC1R in 246 healthy individuals and 116 individuals attending periodic control for malignant melanoma development, 50 of which were diagnosed with FAMMM. It was observed that individuals with any two grouped MC1R variants (missense, NM_002386:c. 456C > A (p.TYR152*), or NM_002386:c.83_84insA (p.Asn29Glnfs*14) had significantly (p<0.001) lighter skin pigmentation of the upper-inner arm than those with none or one MC1R variant. We did not observe any significant association of the MC1R variants with constitutive pigmentation measured on the buttock area. We hypothesize that the effect of MC1R variants on arm pigmentation is primarily reflecting the inability to tan when subjected to UVR. A gender specific effect on skin pigmentation was also observed, and it was found that the skin pigmentation of females on average were darker than that of males (p<0.01). We conclude that MC1R variants are associated with quantitative skin colour in a lightly pigmented Danish population. We did not observe any association between any pigmentary marker and the FAMMM syndrome. We suggest that the genetics of FAMMM is not related to the genetics of the pigmentary pathway.

Fesenko DO, Chudinov AV, Surzhikov SA, Zasedatelev AS
Biochip-Based Genotyping Assay for Detection of Polymorphisms in Pigmentation Genes Associated with Cutaneous Melanoma.
Genet Test Mol Biomarkers. 2016; 20(4):208-12 [PubMed] Related Publications
AIMS: The purpose of the study was to develop a new assay for genotyping nine single nucleotide polymorphisms (SNPs) that are known to be associated with melanoma.
METHODS: Two-stage single tube polymerase chain reaction (PCR) followed by hybridization on a biochip was developed and applied in the study.
RESULTS: A total of nine SNPs were selected from five genes: MC1R (rs1805006, rs1805007, rs1805009, rs11547464), HERC2 (rs12913832), OCA2 (rs1800407), SLC45A2 (rs16891982), TYR (rs1393350), and a SNP from the intergenic locus rs12896399 were used for the synthesis of ssDNAs via a single-stage PCR process. The assays were performed on a biochip-based platform that is capable of SNP genotyping via a single reaction-tube PCR, followed by on chip hybridization. We tested 69 DNAs obtained from healthy persons and demonstrated the assays' ability to discriminate all three genotypes for almost all of the SNPs.
CONCLUSIONS: The developed approach proved robust, suggesting that it might be useful for the personalized genotyping of large cohorts of patients.

Hacker E, Olsen CM, Kvaskoff M, et al.
Histologic and Phenotypic Factors and MC1R Status Associated with BRAF(V600E), BRAF(V600K), and NRAS Mutations in a Community-Based Sample of 414 Cutaneous Melanomas.
J Invest Dermatol. 2016; 136(4):829-37 [PubMed] Related Publications
Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF(V600E) (26%), BRAF(V600K) (8%), BRAF(other) (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF(V600E) mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF(V600K) mutations were also associated with high nevus counts. Both BRAF(V600K) and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports.

Berlin NL, Cartmel B, Leffell DJ, et al.
Family history of skin cancer is associated with early-onset basal cell carcinoma independent of MC1R genotype.
Cancer Epidemiol. 2015; 39(6):1078-83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As a marker of genetic susceptibility and shared lifestyle characteristics, family history of cancer is often used to evaluate an individual's risk for developing a particular malignancy. With comprehensive data on pigment characteristics, lifestyle factors, and melanocortin 1 receptor (MC1R) gene sequence, we sought to clarify the role of family history of skin cancer in early-onset basal cell carcinoma (BCC).
MATERIALS AND METHODS: Early onset BCC cases (n=376) and controls with benign skin conditions (n=383) under age 40 were identified through Yale dermatopathology. Self-report data on family history of skin cancer (melanoma and non-melanoma skin cancer), including age of onset in relatives, was available from a structured interview. Participants also provided saliva samples for sequencing of MC1R.
RESULTS: A family history of skin cancer was associated with an increased risk of early-onset BCC (OR 2.49, 95% CI 1.80-3.45). In multivariate models, family history remained a strong risk factor for early-onset BCC after adjustment for pigment characteristics, UV exposure, and MC1R genotype (OR 2.41, 95% CI 1.74-3.35).
CONCLUSIONS: Risk for BCC varied based upon the type and age of onset of skin cancer among affected relatives; individuals with a first-degree relative diagnosed with skin cancer prior to age 50 were at highest risk for BCC (OR 4.79, 95% CI 2.90-7.90). Even after taking into account potential confounding effects of MC1R genotype and various lifestyle factors that close relatives may share, family history of skin cancer remained strongly associated with early-onset BCC.

Satagopan JM, Iasonos A, Zhou Q
Prognostic and Predictive Values and Statistical Interactions in the Era of Targeted Treatment.
Genet Epidemiol. 2015; 39(7):509-17 [PubMed] Free Access to Full Article Related Publications
The current era of targeted treatment has accelerated the interest in studying gene-treatment, gene-gene, and gene-environment interactions using statistical models in the health sciences. Interactions are incorporated into models as product terms of risk factors. The statistical significance of interactions is traditionally examined using a likelihood ratio test (LRT). Epidemiological and clinical studies also evaluate interactions in order to understand the prognostic and predictive values of genetic factors. However, it is not clear how different types and magnitudes of interaction effects are related to prognostic and predictive values. The contribution of interaction to prognostic values can be examined via improvements in the area under the receiver operating characteristic curve due to the inclusion of interaction terms in the model (ΔAUC). We develop a resampling based approach to test the significance of this improvement and show that it is equivalent to LRT. Predictive values provide insights into whether carriers of genetic factors benefit from specific treatment or preventive interventions relative to noncarriers, under some definition of treatment benefit. However, there is no unique definition of the term treatment benefit. We show that ΔAUC and relative excess risk due to interaction (RERI) measure predictive values under two specific definitions of treatment benefit. We investigate the properties of LRT, ΔAUC, and RERI using simulations. We illustrate these approaches using published melanoma data to understand the benefits of possible intervention on sun exposure in relation to the MC1R gene. The goal is to evaluate possible interventions on sun exposure in relation to MC1R.

Governa M, Caprarella E, Dalla Pozza E, et al.
Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance.
Melanoma Res. 2015; 25(5):443-6 [PubMed] Related Publications
Many genetic alterations, including predisposing or somatic mutations, may contribute toward the development of melanoma. Although CDKN2A and CDK4 are high-penetrance genes for melanoma, MC1R is a low-penetrance gene that has been associated most consistently with the disease. Moreover, BRAF is the most frequently somatically altered oncogene and is a validated therapeutic target in melanoma. This paper reports a case of multiple primary melanoma with germline CDK4 mutation, MC1R variant, and somatic BRAF mutation in nine out of 10 melanomas, indicating that a common pathogenesis, because of a predisposing genetic background, may be shared among distinct subsequent melanomas of probable clonal origin. After 3 months of targeted therapy with BRAF inhibitor, our patient developed resistance with rapid progression of the disease leading to death. This is the first case in which early resistance to BRAF inhibitor has been reported in a patient with CDK4 germline mutation.

Sinnya S, Jagirdar K, De'Ambrosis B, et al.
High incidence of primary melanomas in an MC1R RHC homozygote/CDKN2A mutant genotype patient.
Arch Dermatol Res. 2015; 307(8):741-5 [PubMed] Related Publications
Melanoma incidence in Australia remains the highest in the world; hence understanding its causation is paramount for future therapeutic developments. Multiple primary melanomas are also common occurrences among the Australian population with identified risk factors such as personal and family history of melanoma, fair skin type, dysplastic naevus syndrome and history of significant ultraviolet exposure. The roles of both environmental and genetic factors have been elucidated in melanoma development, but the synergy of interactions between the two remains complex given the heterogeneous nature of the disease. We present a rare case of a 57-year-old female with 20 cutaneous melanomas and review the role of genetic and environmental factors in development of her multiple primary melanomas.

Tagliabue E, Fargnoli MC, Gandini S, et al.
MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.
Br J Cancer. 2015; 113(2):354-63 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics.
METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses.
RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair.
CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.

Stark MS, Bonazzi VF, Boyle GM, et al.
miR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma.
Oncotarget. 2015; 6(19):17753-63 [PubMed] Free Access to Full Article Related Publications
To identify 'melanoma-specific' microRNAs (miRNAs) we used an unbiased microRNA profiling approach to comprehensively study cutaneous melanoma in relation to other solid malignancies, which revealed 233 differentially expressed (≥ 2 fold, p < 0.05) miRNAs. Among the top 20 most significantly different miRNAs was hsa-miR-514a-3p. miR-514a is a member of a cluster of miRNAs (miR-506-514) involved in initiating melanocyte transformation and promotion of melanoma growth. We found miR-514a was expressed in 38/55 (69%) melanoma cell lines but in only 1/34 (3%) other solid cancers. To identify miR-514a regulated targets we conducted a miR-514a-mRNA 'pull-down' experiment, which revealed hundreds of genes, including: CTNNB1, CDK2, MC1R, and NF1, previously associated with melanoma. NF1 was selected for functional validation because of its recent implication inacquired resistance to BRAFV600E-targeted therapy. Luciferase-reporter assays confirmed NF1 as a direct target of miR-514a and over-expression of miR-514a in melanoma cell lines inhibited NF1 expression, which correlated with increased survival of BRAFV600E cells treated with PLX4032. These data provide another mechanism for the dysregulation of the MAPK pathway which may contribute to the profound resistance associated with current RAF-targeted therapies.

Pośpiech E, Ligęza J, Wilk W, et al.
Variants of SCARB1 and VDR Involved in Complex Genetic Interactions May Be Implicated in the Genetic Susceptibility to Clear Cell Renal Cell Carcinoma.
Biomed Res Int. 2015; 2015:860405 [PubMed] Free Access to Full Article Related Publications
The current data are still inconclusive in terms of a genetic component involved in the susceptibility to renal cell carcinoma. Our aim was to evaluate 40 selected candidate polymorphisms for potential association with clear cell renal cell carcinoma (ccRCC) based on independent group of 167 patients and 200 healthy controls. The obtained data were searched for independent effects of particular polymorphisms as well as haplotypes and genetic interactions. Association testing implied position rs4765623 in the SCARB1 gene (OR = 1.688, 95% CI: 1.104-2.582, P = 0.016) and a haplotype in VDR comprising positions rs739837, rs731236, rs7975232, and rs1544410 (P = 0.012) to be the risk factors in the studied population. The study detected several epistatic effects contributing to the genetic susceptibility to ccRCC. Variation in GNAS1 was implicated in a strong synergistic interaction with BIRC5. This effect was part of a model suggested by multifactor dimensionality reduction method including also a synergy between GNAS1 and SCARB1 (P = 0.036). Significance of GNAS1-SCARB1 interaction was further confirmed by logistic regression (P = 0.041), which also indicated involvement of SCARB1 in additional interaction with EPAS1 (P = 0.008) as well as revealing interactions between GNAS1 and EPAS1 (P = 0.016), GNAS1 and MC1R (P = 0.031), GNAS1 and VDR (P = 0.032), and MC1R and VDR (P = 0.035).

Helgadottir H, Höiom V, Tuominen R, et al.
CDKN2a mutation-negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies.
Int J Cancer. 2015; 137(9):2220-6 [PubMed] Related Publications
Germline CDKN2A mutations are found in 5-20% of melanoma families. Numerous studies have shown that carriers of CDKN2A mutations have increased risks of non-melanoma cancers, but so far there have been no studies investigating cancer risks in CDKN2A wild type (wt) melanoma families. In this prospective cohort study, index melanoma cases (n = 224) and their first-degree relatives (n = 944) were identified from 154 confirmed CDKN2A wt melanoma families. Cancer diagnoses in family members and matched controls were obtained from the Swedish Cancer Registry. Relative risks (RR), odds ratios (OR) and two-sided 95% confidence intervals (95% CI) were calculated. In index cases and first-degree relatives, the prospective RR for melanoma was 56.9 (95% CI 31.4-102.1) and 7.0 (95% CI 4.2-11.4), respectively, and for squamous cell skin cancers 9.1 (95% CI 6.0-13.7) and 3.4 (95% CI 2.2-5.2), respectively. In neither group, elevated risks were seen for non-skin cancers. In a subgroup analysis, CDKN2A wt melanoma families with young (<40 years) melanoma cases were found to have increased risk of non-skin cancers (RR 1.5, 95% CI 1.0-1.5). Further, MC1R gene variants were increased in familial melanoma cases compared to controls (OR 2.4, 95% CI 1.6-3.4). Our findings suggest that in the majority of CDKN2A wt melanoma families, a segregation of variants in low-risk melanoma genes such as MC1R causes increased skin cancer susceptibility, rather than mutations in high-risk cancer predisposing genes, such mutations are more probable to be found in melanoma families with young melanoma cases. This study further supports an implication of CDKN2A mutation screening as a clinical test that determines counseling and follows up routines of melanoma families.

Molinaro AM, Ferrucci LM, Cartmel B, et al.
Indoor tanning and the MC1R genotype: risk prediction for basal cell carcinoma risk in young people.
Am J Epidemiol. 2015; 181(11):908-16 [PubMed] Free Access to Full Article Related Publications
Basal cell carcinoma (BCC) incidence is increasing, particularly in young people, and can be associated with significant morbidity and treatment costs. To identify young individuals at risk of BCC, we assessed existing melanoma or overall skin cancer risk prediction models and built a novel risk prediction model, with a focus on indoor tanning and the melanocortin 1 receptor gene, MC1R. We evaluated logistic regression models among 759 non-Hispanic whites from a case-control study of patients seen between 2006 and 2010 in New Haven, Connecticut. In our data, the adjusted area under the receiver operating characteristic curve (AUC) for a model by Han et al. (Int J Cancer. 2006;119(8):1976-1984) with 7 MC1R variants was 0.72 (95% confidence interval (CI): 0.66, 0.78), while that by Smith et al. (J Clin Oncol. 2012;30(15 suppl):8574) with MC1R and indoor tanning had an AUC of 0.69 (95% CI: 0.63, 0.75). Our base model had greater predictive ability than existing models and was significantly improved when we added ever-indoor tanning, burns from indoor tanning, and MC1R (AUC = 0.77, 95% CI: 0.74, 0.81). Our early-onset BCC risk prediction model incorporating MC1R and indoor tanning extends the work of other skin cancer risk prediction models, emphasizes the value of both genotype and indoor tanning in skin cancer risk prediction in young people, and should be validated with an independent cohort.

Dessinioti C, Sypsa V, Kypreou K, et al.
A case-control study of MC1R variants in Greek patients with basal cell carcinoma: increased risk independently of pigmentary characteristics.
Exp Dermatol. 2015; 24(6):476-8 [PubMed] Related Publications
Melanocortin 1 receptor (MC1R) gene variants are a major contributor to pigmentation characteristics and the modulation of sporadic basal cell carcinoma (BCC) risk. This is a hospital-based, case-control study to investigate the association of MC1R variants and pigmentary characteristics with the risk of BCC development in a Southern European population in Greece. In total, 141 patients with BCC and 166 controls were studied. Increased BCC risk was found for the presence of 2 or more MC1R variants (OR:3.07, 95% CI:1.13-8.34), or 2 or more variants of which at least 1 was major function (OR:7.15, 95% CI:1.37-5.52), after adjustment for the 'red hair colour' (RHC) phenotype. Increased BCC risk persisted in the presence of 2 or more MC1R variants (OR:4.15, 95% CI:1.35-12.72), after adjustment for potential confounding factors including skin color (P:0.237) and atypical nevi (OR:9.57, 95% CI:2.19-41.81, P:0.003). MC1R genotype is a risk factor for the development of BCC in Greek patients independently of pigmentary characteristics, and the combination of MC1R variants may modulate this risk.

Wadt KA, Aoude LG, Krogh L, et al.
Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition.
PLoS One. 2015; 10(3):e0122662 [PubMed] Free Access to Full Article Related Publications
Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.

Taylor NJ, Busam KJ, From L, et al.
Inherited variation at MC1R and histological characteristics of primary melanoma.
PLoS One. 2015; 10(3):e0119920 [PubMed] Free Access to Full Article Related Publications
Variation in the melanocortin-1receptor (MC1R) gene is associated with pigmentary phenotypes and risk of malignant melanoma. Few studies have reported on MC1R variation with respect to tumor characteristics, especially clinically important prognostic features. We examined associations between MC1R variants and histopathological melanoma characteristics. Study participants were enrolled from nine geographic regions in Australia, Canada, Italy and the United States and were genotyped for MC1R variants classified as high-risk [R] (D84E, R142H, R151C, R160W, and D294H, all nonsense and insertion/deletion) or low-risk [r] (all other nonsynonymous) variants. Tissue was available for 2,160 white participants of the Genes, Environment and Melanoma (GEM) Study with a first incident primary melanoma diagnosis, and underwent centralized pathologic review. No statistically significant associations were observed between MC1R variants and AJCC established prognostic tumor characteristics: Breslow thickness, presence of mitoses or presence of ulceration. However, MC1R was significantly associated with anatomic site of melanoma (p = 0.002) and a positive association was observed between carriage of more than one [R] variant and melanomas arising on the arms (OR = 2.39; 95% CI: 1.40, 4.09). We also observed statistically significant differences between sun-sensitive and sun-resistant individuals with respect to associations between MC1R genotype and AJCC prognostic tumor characteristics. Our results suggest inherited variation in MC1R may play an influential role in anatomic site presentation of melanomas and may differ with respect to skin pigmentation phenotype.

Montero I, Requena C, Traves V, et al.
Age-related characteristics of cutaneous melanoma in a Spanish Mediterranean population.
Int J Dermatol. 2015; 54(7):778-84 [PubMed] Related Publications
BACKGROUND: Melanoma is considered a heterogeneous tumor with genetic and environmental factors involved in its pathogenesis. The impact of these factors varies depending on age.
OBJECTIVE: The aim of this study was to characterize the epidemiological, phenotypic, and histological features of patients with melanoma according to three age groups: ≤40, 41-65, and >65 years.
METHODS: A total of 1122 consecutive patients with invasive melanoma definitively treated in our institution since January 2000 were selected from our melanoma database. Epidemiological, phenotypic, and histological data were retrieved and analyzed as a function of age.
RESULTS: Female patients predominated in the younger age group. The location of cutaneous malignant melanoma differed with age. In the younger and middle age groups, tumors presented mainly on the trunk, while in the older group they were mainly found on the head/neck. Signs of actinic damage such as actinic keratoses, solar lentigines, or other skin tumors increased with age, while genetic factors such as family history of melanoma or a high number of common melanocytic nevi were more frequent in the younger group.
CONCLUSION: Our results suggest that melanoma development in younger patients is the result of genetic factors, particularly related to multiple nevi, whereas in older patients environmental factors such as severe chronic sun exposure play a major role.

Guida S, Bartolomeo N, Zanna PT, et al.
Sporadic melanoma in South-Eastern Italy: the impact of melanocortin 1 receptor (MC1R) polymorphism analysis in low-risk people and report of three novel variants.
Arch Dermatol Res. 2015; 307(6):495-503 [PubMed] Related Publications
Environmental and genetic risk factors are involved in the development of melanoma. The role of the melanocortin 1 receptor (MC1R) gene has been investigated and differences according to geographic areas have been described. To evaluate the role of some clinical and genetic risk factors in melanoma development, we performed a case-control study involving 101 melanoma patients and 103 controls coming from South-Eastern Italy (Puglia), after achieving informed consent. We confirmed the role of known clinical risk factors for melanoma. Furthermore, 42 MC1R polymorphisms were observed. Three of these variants (L26V, H232L, D294Y) were not previously reported in the literature. Their predicted impact on receptor function was evaluated using bioinformatic tools. We report an overall frequency of MC1R variants in our population higher than in Northern or Central Italy. The most common polymorphism found was V60L, that has been recently reported to spread among South Mediterranean population. This variant influenced phenotypic characteristics of our population while it did not impinge on melanoma risk. An increased risk of melanoma was associated with two or more MC1R variants, when at least one was RHC, compared to people carrying the MC1R consensus sequence or a single MC1R polymorphism. Interestingly, we observed an increased risk of melanoma in subjects with darker skin and lower nevus count, usually considered at low risk, when carrying MC1R polymorphisms.

Jacobs LC, Liu F, Pardo LM, et al.
IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color.
Hum Mol Genet. 2015; 24(11):3296-303 [PubMed] Related Publications
Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north-western European origin (aged 51-99 years, 45% male). Physicians graded the number of AK into four severity levels: none (76%), 1-3 (14%), 4-9 (6%) and ≥10 (5%), and skin color was quantified using a spectrophotometer on sun-unexposed skin. A GWAS for AK severity was conducted, where promising signals at IRF4 and MC1R (P < 4.2 × 10(-7)) were successfully replicated in an additional cohort of 623 RS individuals (IRF4, rs12203592, Pcombined = 6.5 × 10(-13) and MC1R, rs139810560, Pcombined = 4.1 × 10(-9)). Further, in an analysis of ten additional well-known human pigmentation genes, TYR also showed significant association with AK (rs1393350, P = 5.3 × 10(-4)) after correction for multiple testing. Interestingly, the strength and significance of above-mentioned associations retained largely the same level after skin color adjustment. Overall, our data strongly suggest that IRF4, MC1R and TYR genes likely have pleiotropic effects, a combination of pigmentation and oncogenic functions, resulting in an increased risk of AK.

Jacobs LC, Hamer MA, Gunn DA, et al.
A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots.
J Invest Dermatol. 2015; 135(7):1735-42 [PubMed] Related Publications
Facial pigmented spots are a common skin aging feature, but genetic predisposition has yet to be thoroughly investigated. We conducted a genome-wide association study for pigmented spots in 2,844 Dutch Europeans from the Rotterdam Study (mean age: 66.9±8.0 years; 47% male). Using semi-automated image analysis of high-resolution digital facial photographs, facial pigmented spots were quantified as the percentage of affected skin area (mean women: 2.0% ±0.9, men: 0.9% ±0.6). We identified genome-wide significant association with pigmented spots at three genetic loci: IRF4 (rs12203592, P=1.8 × 10(-27)), MC1R (compound heterozygosity score, P=2.3 × 10(-24)), and RALY/ASIP (rs6059655, P=1.9 × 10(-9)). In addition, after adjustment for the other three top-associated loci the BNC2 locus demonstrated significant association (rs62543565, P=2.3 × 10(-8)). The association signals observed at all four loci were successfully replicated (P<0.05) in an independent Dutch cohort (Leiden Longevity Study n=599). Although the four genes have previously been associated with skin color variation and skin cancer risk, all association signals remained highly significant (P<2 × 10(-8)) when conditioning the association analyses on skin color. We conclude that genetic variations in IRF4, MC1R, RALY/ASIP, and BNC2 contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production.

Premi S, Wallisch S, Mano CM, et al.
Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure.
Science. 2015; 347(6224):842-7 [PubMed] Free Access to Full Article Related Publications
Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. We found that in melanocytes, CPDs are generated for >3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These "dark CPDs" constitute the majority of CPDs and include the cytosine-containing CPDs that initiate UV-signature C→T mutations. Dark CPDs arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but induces CPDs by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically generated excited electronic states are relevant to mammalian biology.

Tell-Marti G, Puig-Butille JA, Potrony M, et al.
The MC1R melanoma risk variant p.R160W is associated with Parkinson disease.
Ann Neurol. 2015; 77(5):889-94 [PubMed] Related Publications
Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population.

Burke MT, Isbel N, Barraclough KA, et al.
Genetics and nonmelanoma skin cancer in kidney transplant recipients.
Pharmacogenomics. 2015; 16(2):161-72 [PubMed] Related Publications
Kidney transplant recipients (KTRs) have a 65- to 250-fold greater risk than the general population of developing nonmelanoma skin cancer. Immunosuppressive drugs combined with traditional risk factors such as UV radiation exposure are the main modifiable risk factors for skin cancer development in transplant recipients. Genetic variation affecting immunosuppressive drug pharmacokinetics and pharmacodynamics has been associated with other transplant complications and may contribute to differences in skin cancer rates between KTRs. Genetic polymorphisms in genes encoding the prednisolone receptor, GST enzyme, MC1R, MTHFR enzyme and COX-2 enzyme have been shown to increase the risk of nonmelanoma skin cancer in KTRs. Genetic association studies may improve our understanding of how genetic variation affects skin cancer risk and potentially guide immunosuppressive treatment and skin cancer screening in at risk individuals.

Sarkar D, Leung EY, Baguley BC, et al.
Epigenetic regulation in human melanoma: past and future.
Epigenetics. 2015; 10(2):103-21 [PubMed] Free Access to Full Article Related Publications
The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

Barón AE, Asdigian NL, Gonzalez V, et al.
Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes.
Cancer Epidemiol Biomarkers Prev. 2014; 23(12):2829-39 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar UV light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective interactions between UV exposures and nevus and freckling genes remain largely undescribed.
METHODS: We conducted a longitudinal study from ages 6 through 10 years in 477 Colorado children who had annual information collected for sun exposure, sun protection behaviors, and full body skin exams. MC1R and HERC2/OCA2 rs12913832 were genotyped and linear mixed models were used to identify main and interaction effects.
RESULTS: All measures of sun exposure (chronic, sunburns, and waterside vacations) contributed to total nevus counts, and cumulative chronic exposure acted as the major driver of nevus development. Waterside vacations strongly increased total nevus counts in children with rs12913832 blue eye color alleles and facial freckling scores in those with MC1R red hair color variants. Sunburns increased the numbers of larger nevi (≥2 mm) in subjects with certain MC1R and rs12913832 genotypes.
CONCLUSIONS: Complex interactions between different UV exposure profiles and genotype combinations determine nevus numbers and size, and the degree of facial freckling.
IMPACT: Our findings emphasize the importance of implementing sun-protective behavior in childhood regardless of genetic make-up, although children with particular genetic variants may benefit from specifically targeted preventive measures to counteract their inherent risk of melanoma. Moreover, we demonstrate, for the first time, that longitudinal studies are a highly powered tool to uncover new gene-environment interactions that increase cancer risk.

Taylor NJ, Reiner AS, Begg CB, et al.
Inherited variation at MC1R and ASIP and association with melanoma-specific survival.
Int J Cancer. 2015; 136(11):2659-67 [PubMed] Free Access to Full Article Related Publications
Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.

Ainger SA, Yong XL, Wong SS, et al.
DCT protects human melanocytic cells from UVR and ROS damage and increases cell viability.
Exp Dermatol. 2014; 23(12):916-21 [PubMed] Related Publications
Dopachrome tautomerase (DCT) is involved in the formation of the photoprotective skin pigment eumelanin and has also been shown to have a role in response to apoptotic stimuli and oxidative stress. The effect of DCT on UVR DNA damage responses and survival pathways in human melanocytic cells was examined by knockdown experiments using melanoma cells, neonatal foreskin melanoblasts (MB) in monoculture and in co-culture with human keratinocytes. MB cell strains genotyped as either MC1R WT or MC1R RHC homozygotes, which are known to be deficient in DCT, were transduced with lentivirus vectors for either DCT knockdown or overexpression. We found melanoma cell survival was reduced by DCT depletion and by UVR over time. UVR-induced p53 and pp53-Ser15 levels were reduced with DCT depletion. Knockdown of DCT in MC1R WT and MC1R RHC MB cells reduced their survival after UVR exposure, whereas increased DCT protein levels enhanced survival. DCT depletion reduced p53 and pp53-Ser15 levels in WM266-4 melanoma and MC1R WT MB cells, while MC1R RHC MB cells displayed variable levels. Both MC1R WT and RHC genotypes of MB cells were responsive to UVR at 3 h with increases in both p53 and pp53-Ser15 proteins. MC1R WT MB cell strains in coculture with keratinocytes have an increased cell survival after UVR exposure when compared to those in monoculture, a protective effect which appears to be conferred by the keratinocytes.

Binstock M, Hafeez F, Metchnikoff C, Arron ST
Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review.
Br J Dermatol. 2014; 171(4):713-21 [PubMed] Related Publications
Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A. The two most common NMSCs are basal cell carcinoma and squamous cell carcinoma. The associations of single-nucleotide polymorphisms (SNPs) in pigmentation pathway genes with NMSC are not well characterized. There is a series of epidemiological studies that have tested these relationships, but there is no recent summary of these findings. To explain overarching trends, we undertook a systematic review of published studies. The summarized data support the concept that specific SNPs in the pigmentation pathway are of importance for the pathogenesis of NMSC. The SNPs with the most promising evidence include MC1R rs1805007(T) (Arg151Cys) and rs1805008(T) (Arg160Trp), and ASIP AH haplotype [rs4911414(T) and rs1015362(G)]. There are a few other SNPs found in TYR, OCA2 and SLC45A2 that may show additional correlation after future research. With additional research there is potential for the translation of future findings to the clinic in the form of SNP screenings, where patients at high risk for NMSC can be identified beyond their phenotype by genotypically screening for predisposing SNPs.

Orlow I, Satagopan JM, Berwick M, et al.
Genetic factors associated with naevus count and dermoscopic patterns: preliminary results from the Study of Nevi in Children (SONIC).
Br J Dermatol. 2015; 172(4):1081-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Melanocytic naevi are an important risk factor for melanoma. Naevi with distinct dermoscopic patterns can differ in size, distribution and host pigmentation characteristics.
OBJECTIVES: We examined MC1R and 85 other candidate loci in a cohort of children to test the hypothesis that the development and dermoscopic type of naevi are modulated by genetic variants.
METHODS: Buccal DNAs were obtained from a cohort of 353 fifth graders (mean age 10·4 years). Polymorphisms were chosen based on a known or anticipated role in naevi and melanoma. Associations between single-nucleotide polymorphisms (SNPs) and baseline naevus count were determined by multivariate regression adjusting for sex, race/ethnicity and sun sensitivity. Dermoscopic images were available for 853 naevi from 290 children. Associations between SNPs and dermoscopic patterns were determined by polytomous regression.
RESULTS: Four SNPs were significantly associated with increasing (IRF4) or decreasing (PARP1, CDK6 and PLA2G6) naevus count in multivariate shrinkage analyses with all SNPs included in the model; IRF4 rs12203952 showed the strongest association with log naevus count (relative risk 1·56, P < 0·001). Using homogeneous naevi as the reference, IRF4 rs12203952 and four other SNPs in TERT, CDKN1B, MTAP and PARP1 were associated with either globular or reticular dermoscopic patterns (P < 0·05).
CONCLUSIONS: Our results provide evidence that subsets of naevi defined by dermoscopic patterns differ in their associations with germline genotypes and support the hypothesis that dermoscopically defined subsets of naevi are biologically distinct. These results require confirmation in larger cohorts. If confirmed, these findings will improve the current knowledge of naevogenesis and assist in the identification of individuals with high-risk phenotypes.

Banan P, Lee KJ, McClenahan P, et al.
Dermoscopy, reflectance confocal microscopy and histopathology of a melanoma in situ from an individual homozygous for GSTP1*105Val/MC1R*92Met.
Australas J Dermatol. 2016; 57(1):64-7 [PubMed] Related Publications
Glutathione S-transferase 1 is an enzyme involved in the detoxification of reactive oxygen species, and the rs1695*Val polymorphism has been proposed as a melanoma-associated variant with significant effect. We report a case of malignant melanoma in an individual homozygous for the rs1695*Val variant and discuss the non-invasive and histopathological tools used in diagnosis.

Elincx-Benizri S, Inzelberg R, Greenbaum L, et al.
The melanocortin 1 receptor (Mc1r) variants do not account for the co-occurrence of Parkinson's disease and malignant melanoma.
J Mol Neurosci. 2014; 54(4):820-5 [PubMed] Related Publications
Parkinson's disease (PD) is characterized by loss of melanin-positive dopaminergic neurons in the substantia nigra. Malignant melanoma (MM), a melanocyte-derived neoplasm, occurs with higher than expected frequency among PD patients. Red-haired individuals exhibit a threefold risk for developing MM than dark-haired people; PD risk also increases with lighter hair color. One plausible explanation for the associations between MM, hair color, and PD is the melanocortin-1 receptor (MC1R) gene that plays a key role in hair and skin pigmentation as well as in MM predisposition. We hypothesized that specific MC1R variants may predispose to both MM and PD. Genotyping of the MC1R gene was performed for 16 PD patients with MM (PD+ MM+) and for three sets of age, sex, and ethnically matched controls, including 36 patients with PD (PD+ MM-), 37 with MM (PD- MM+) and 37 with neither diagnosis (PD- MM-). No association was found between MC1R variants and the co-occurrence of PD and MM. The risk for MM was higher in carriers of two MC1R variants versus with no MC1R variant (odds ratio (OR)=5.0, 95% confidence interval (CI) 1.7-14.4, p=0.003). The risk for PD in carriers of two MC1R variants was markedly lower (OR=0.213, 95% CI 0.063-0.725) compared with individuals with no MC1R variant (p=0.013). In this study, MC1R variants were not associated with both MM and PD. Further studies in larger cohorts are necessary to confirm these preliminary results.

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