Melanocortin-1 Receptor Gene Variants Research Articles

Germline MC1R variants and frequency of somatic BRAF, NRAS, and TERT mutations in melanoma: Literature review and meta-analysis.

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.

The role of MC1R gene variants and phenotypical features in predicting high nevus count.

Variants in the Melanocortin 1 Receptor (MC1R) gene have been associated with an increased risk of melanoma, but the role in nevus count is unclear. We investigated if specific MC1R gene variants or the number of MC1R gene variants and phenotypical features were associated with nevus count. A total of 494 participants of the 'Leiden skin cancer study' were included and the MC1R gene coding sequence was analysed by single-strand conformation polymorphism analysis followed by sequencing of unknown variants. The association between MC1R gene variants and nevus count and the association between age, gender and phenotypical features and nevus count were studied using the Chi-square test. Study of nine frequently occurring MC1R gene variants in participants without skin cancer (n = 203) showed that the 'r' Val60Leu variant was significantly associated with high nevus count (>50 nevi) (P = 0.017). This association was very strong among women (P < 0.001), but not present among men. Having one or two MC1R variants in general did not show a significant difference in the nevus count. Hair colour, skin type, eye colour and age were not significantly associated with nevus count, whereas gender showed a significant association (P = 0.008), with the highest nevus counts in female. The Val60Leu variant of the MC1R gene could be a promising candidate as an independent predictor of high nevus count, particularly in women. This information about the genetic makeup could promote personalized follow-up strategies and might help to prevent skin cancer in the future.

Implementing an Internet-Delivered Skin Cancer Genetic Testing Intervention to Improve Sun Protection Behavior in a Diverse Population: Protocol for a Randomized Controlled Trial.

BackgroundLimited translational genomic research currently exists to guide the availability, comprehension, and appropriate use of personalized genomics in diverse general population subgroups. Melanoma skin cancers are preventable, curable, common in the general population, and disproportionately increasing in Hispanics.ObjectiveVariants in the melanocortin-1 receptor (MC1R) gene are present in approximately 50% of the population, are major factors in determining sun sensitivity, and confer a 2-to-3-fold increase in melanoma risk in the general population, even in populations with darker skin. Therefore, feedback regarding MC1R risk status may raise risk awareness and protective behavior in the general population.MethodsWe are conducting a randomized controlled trial examining Internet presentation of the risks and benefits of personalized genomic testing for MC1R gene variants that are associated with increased melanoma risk. We will enroll a total of 885 participants (462 participants are currently enrolled), who will be randomized 6:1 to personalized genomic testing for melanoma risk versus waiting list control. Control participants will be offered testing after outcome assessments. Participants will be balanced across self-reported Hispanic versus non-Hispanic ethnicity (n=750 in personalized genomic testing for melanoma risk arm; n=135 in control arm), and will be recruited from a general population cohort in Albuquerque, New Mexico, which is subject to year-round sun exposure. Baseline surveys will be completed in-person with study staff and follow-up measures will be completed via telephone.ResultsAim 1 of the trial will examine the personal utility of personalized genomic testing for melanoma risk in terms of short-term (3-month) sun protection and skin screening behaviors, family and physician communication, and melanoma threat and control beliefs (ie, putative mediators of behavior change). We will also examine potential unintended consequences of testing among those who receive average-risk personalized genomic testing for melanoma risk findings, and examine predictors of sun protection at 3 months as the outcome. These findings will be used to develop messages for groups that receive average-risk feedback. Aim 2 will compare rates of test consideration in Hispanics versus non-Hispanics, including consideration of testing pros and cons and registration of a decision to either accept or decline testing. Aim 3 will examine personalized genomic testing for melanoma risk feedback comprehension, recall, satisfaction, and cancer-related distress in those who undergo testing, and whether these outcomes differ by ethnicity (Hispanic vs non-Hispanic), or sociocultural or demographic factors. Final outcome data collection is anticipated to be complete by October 2017, at which point data analysis will commence.ConclusionsThis study has important implications for personalized genomics in the context of melanoma risk, and may be broadly applicable as a model for delivery of personalized genomic feedback for other health conditions.

MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.

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.

Abstract 869: Characterization of malignant melanoma families with CDK4 germ-line mutation

Abstract Background: CDKN2A (p16) and CDK4 are high-risk susceptibility genes for cutaneous melanoma. CDKN2A is the major identified high-risk gene and CDKN2A-mutated families have been extensively characterized. Melanoma families with CDK4 mutation are very rare. Only 10 such families have been published and a systematic investigation of their phenotype is lacking. Aim of study: We evaluated all known CDK4-mutated families with regard to phenotypic features of their melanocytic disease. We also examined if common variants of the melanocortin-1 receptor (MC1R) gene had an effect on age of melanoma onset. Methods: CDK4-melanoma families, previously ascertained by different research groups, were selected for this study either by contacting the authors of published papers or by requests via the GenoMEL Melanoma Genetics Consortium. Phenotypic data related to melanoma and pigmentation were collected via a standardized form. For all family members with available DNA, exon 2 of CDK4 and the complete coding region of the MC1R gene were sequenced. Results: Thirteen CDK4 families (including three unpublished) were enrolled in the study. Altogether, 83 subjects with malignant melanoma, having a total of 125 melanomas, were verified in the pedigrees. The mean and median age of melanoma diagnosis was 38.5 years and 36.5 years, respectively. Of the 83 melanoma-positive subjects, 29 (34.9%) had multiple primary melanoma. Superficially spreading melanoma was the most common histological diagnosis (52.2%). DNA was available from 198 members of the pedigrees, and 81 tested positive for either the CDK4 R24H or R24C mutation; 117 subjects including 39 spouses tested negative. Subjects with the CDK4 mutation or with verified melanoma had a much higher prevalence of atypical nevi (79.5% and 77.2%, respectively) than CDK4-negative family members (26.0%; p&amp;lt;0.001 for both groups). The pedigrees included only one verified case of pancreatic cancer, occurring in a non-tested subject with melanoma. There did not appear to be evidence for a predisposition to other non-melanoma cancers. The analysis of MC1R gene variants is ongoing. Conclusion: CDK4-positive melanoma families are phenotypically similar to families with a CDKN2A mutation with regard to age of melanoma diagnosis, histological tumor type and the presence of atypical nevi/multiple melanomas. In a clinical setting, the CDK4 gene should therefore be examined if a melanoma family is negative for a CDKN2A mutation. Although based on only 13 CDK4 families, mutation carriers do not appear to have an increased predisposition to pancreatic cancer as noted in some pedigrees with CDKN2A mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 869. doi:10.1158/1538-7445.AM2011-869

Genetic Variations Associated With Red Hair Color and Fear of Dental Pain, Anxiety Regarding Dental Care and Avoidance of Dental Care

Red hair color is caused by variants of the melanocortin-1 receptor (MC1R) gene. People with naturally red hair are resistant to subcutaneous local anesthetics and, therefore, may experience increased anxiety regarding dental care. The authors tested the hypothesis that having natural red hair color, a MC1R gene variant or both could predict a patient's experiencing dental care-related anxiety and dental care avoidance. The authors enrolled 144 participants (67 natural red-haired and 77 dark-haired) aged 18 to 41 years in a cross-sectional observational study. Participants completed validated survey instruments designed to measure general and dental care-specific anxiety, fear of dental pain and previous dental care avoidance. The authors genotyped participants' blood samples to detect variants associated with natural red hair color. Eighty-five participants had MC1R gene variants (65 of the 67 red-haired participants and 20 of the 77 dark-haired participants) (P < .001). Participants with MC1R gene variants reported significantly more dental care-related anxiety and fear of dental pain than did participants with no MC1R gene variants. They were more than twice as likely to avoid dental care as were the participants with no MC1R gene variants, even after the authors controlled for general trait anxiety and sex. Dental care-related anxiety, fear of dental pain and avoidance of dental care may be influenced by genetic variations. Dentists should evaluate all patients, but especially those with naturally red hair, for dental care-related anxiety and use appropriate modalities to manage the patients' anxiety.

Main pigmentary features andmelanocortin 1 receptor(MC1R) gene polymorphisms in the population of the Canary Islands

Sun exposure, light skin pigmentation, and melanocortin 1 receptor (MC1R) gene variants are independent risk factors for skin cancer. The Canary Islands have a sunny and temperate climate, but data regarding the phenotypic and genotypic risk factors among the population are lacking. The main phenotypic features (skin color, hair color, eye color, and freckling) of 5116 healthy individuals are described. The genotypic findings of six MC1R gene variants (V60L, D84E, R150C, R160W, R163Q, and T314T) in 116 healthy individuals from a population-based cohort with at least three generations of Canary Islands' ancestry are evaluated. The variants were analyzed by SNaPshot. Fifty per cent of the population showed at least one phenotypic risk factor (fair skin, 34.3%; freckling, 17.4%; green or blue eyes, 16.8%; red or blonde hair, 7.8%), although brown skin (65.7%), dark eyes (83.2%), and dark hair (92.2%) prevailed. Forty-three per cent of the individuals showed at least one of the MC1R variants studied. Allelic frequencies for V60L, D84E, R150C, R160W, R163Q, and T314T were 9.1%, 1.7%, 3.0%, 0.8%, 3.0%, and 8.2%, respectively. A significant proportion of the population showed risk factors for skin cancer. The inhabitants of the Canary Islands are phenotypically and genotypically close to Mediterranean populations.

Melanocortin Receptor-1 Gene Polymorphisms and the Risk of Cutaneous Melanoma in a Low-Risk Southern European Population

Individuals with melanocortin 1 receptor (MC1R) gene variants have been shown to carry an increased risk for the development of melanoma. In this study, we investigated the relationship of MC1R gene variants and the risk of melanoma in 123 melanoma patients and 155 control subjects from Greece. The entire MC1R gene was sequenced for polymorphisms and the results were correlated with host factors and pigmentary characteristics. MC1R polymorphisms were present in 59.4% of melanoma patients compared to 37.5% of controls, yielding an odds ratio (OR) of 2.43 (95% confidence interval (CI) = 1.50-3.96, P < 0.001) for melanoma among MC1R carriers. The risk of melanoma was enhanced in individuals carrying multiple variant alleles (OR = 6.97; 95% CI = 1.86-26.12, P = 0.004). Only the Val60Leu, Arg142His, and Arg151Cys variants were significantly associated with melanoma risk. In stratified analysis, the risk of melanoma among MC1R carriers was not influenced by skin phototype, skin color, or hair color. No association was found between MC1R genotype and the age of onset of melanoma, the tumor location, or the tumor thickness. In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.

Contribution of melanocortin-1 receptor gene variants to sporadic cutaneous melanoma risk in a population in central Italy: a case–control study

The melanocortin-1 receptor (MC1R) gene is a key determinant of the physiological variation in human skin pigmentation. It is highly polymorphic, and specific MC1R allelic variants have been shown to be low-penetrance melanoma susceptibility alleles. We investigated the contribution of the MC1R genotype to the risk of sporadic cutaneous melanoma in a population in central Italy. One hundred patients with sporadic cutaneous melanoma of any stage and 100 unrelated control individuals were consecutively recruited between 1 September 2000 and 31 December 2001. Information on ethnic background and residential history, phenotypic risk factors for melanoma and ultraviolet exposure habits was collected through a standardized questionnaire and total skin examination. Sequence analysis of the entire coding region of the MC1R gene was performed. A total of 26 MC1R variants, including a novel 123_124insT allele, was identified in our population, with the most frequent allele being V60L. Carriers of high-penetrance 'R' MC1R alleles, that define MC1R variants strongly associated with the red hair colour phenotype, showed a statistically significant increase in melanoma risk [odds ratio (OR), 2.55; 95% confidence interval (CI), 1.19-5.55]. No significant association with melanoma risk was observed for carriers of 'r' variants (OR, 0.90; 95% CI, 0.45-1.82). Amongst individual MC1R variants, the R151C allele was significantly associated with melanoma, with an OR of 2.94 (95% CI, 1.04-8.31). After stratification for clinical and ultraviolet exposure risk factors, the melanoma risk associated with high-penetrance 'R' variants appeared to increase significantly, mainly in the presence of clinically atypical naevi, more than 50 melanocytic naevi, high recreational sun exposure and occupational sun exposure. These results support the contribution of high-penetrance MC1R variant alleles to genetic predisposition to sporadic cutaneous melanoma in a population in central Italy.

The melanocortin-1-receptor gene is the major freckle gene.

Ephelides and solar lentigines are different types of pigmented skin lesions. Ephelides appear early in childhood and are associated with fair skin type and red hair. Solar lentigines appear with increasing age and are a sign of photodamage. Both lesions are strong risk indicators for melanoma and non-melanoma skin cancer. Melanocortin-1-receptor (MC1R) gene variants are also associated with fair skin, red hair and melanoma and non-melanoma skin cancer. The purpose of this study was to investigate the relationship between MC1R gene variants, ephelides and solar lentigines. In a large case-control study, patients with melanoma and non-melanoma skin cancer and subjects without a history of skin cancer were studied. In all participants, the presence of ephelides in childhood and solar lentigines by physical examination was assessed according to strict definitions. The entire coding sequence of the MC1R gene was analyzed by single-strand conformation polymorphism analysis followed by sequence analyses. Carriers of one or two MC1R gene variants had a 3- and 11-fold increased risk of developing ephelides, respectively (both P < 0.0001), whereas the risk of developing severe solar lentigines was increased 1.5- and 2-fold (P = 0.035 and P < 0.0001), respectively. These associations were independent of skin type and hair color, and were comparable in patients with and without a history of skin cancer. The population attributable risk for ephelides to MC1R gene variants was 60%, i.e. 60% of the ephelides in the population was caused by MC1R gene variants. A dosage effect was found between the degree of ephelides and the number of MC1R gene variants. As nearly all individuals with ephelides were carriers of at least one MC1R gene variant, our data suggest that MC1R gene variants are necessary to develop ephelides. The results of the study also suggest that MC1R gene variants play a role, although less important, in the development of solar lentigines.

Melanocortin-1 Receptor Gene Variants Determine the Risk of Nonmelanoma Skin Cancer Independently of Fair Skin and Red Hair

Melanocortin-1 receptor (MC1R) gene variants are associated with fair skin and red hair and, independently of these, with cutaneous malignant melanoma. The association of MC1R gene variants with nonmelanoma skin cancer is largely unknown. A total of 838 subjects were included in the present study: 453 patients with nonmelanoma skin cancer and 385 subjects with no skin cancer. The coding sequence of the human MC1R gene was tested using single-stranded conformation polymorphism analysis followed by sequencing of unknown variants. Risk of skin cancer dependent on the various MC1R gene variants was estimated using the exposure odds ratio. We investigated whether subjects with MC1R variant alleles were at increased risk of developing nonmelanoma skin cancer and, if so, whether this increased risk was mediated by fair skin and red hair. A total of 27 MC1R gene variants were found. The number of carriers of one, two, or three MC1R gene variants was 379 (45.2%), 208 (24.8%), and 7 (0.9%), respectively. A strong association between MC1R gene variants and fair skin and red hair was established, especially the variants Arg151Cys and Arg160Trp (P < .0001). Carriers of two variant alleles were at increased risk for developing cutaneous squamous cell carcinoma (odds ratio 3.77; 95% confidence interval [CI] 2.11-6.78), nodular basal cell carcinoma (odds ratio 2.26; 95% CI 1.45-3.52), and superficial multifocal basal cell carcinoma (odds ratio 3.43; 95% CI 1.92-6.15), compared with carriers of two wild-type alleles. Carriers of one variant allele had half the risk. The highest relative risks of nonmelanoma skin cancer were found in carriers of the Asp84Glu, His260Pro, and Asp294His variant alleles, and the risk was only slightly lower for carriers of the Val60Leu, Val92Met, Arg142His, Arg151Cys, and Arg160Trp variant alleles. When subjects were stratified by skin type and hair color, analysis showed that these factors did not materially change the relative risks. These findings indicate that MC1R gene variants are important independent risk factors for nonmelanoma skin cancer.

Melanocortin-1 receptor gene variants in four Chinese ethnic populations.

There is strong relationship between melanocortin-1 receptor (MC1R) gene variants and human hair color and skin type. Based on a sequencing study of MC1R gene in 50 individuals from the Uygur, Tibetan, Wa and Dai ethnic populations, we discuss the occurrence of 7 mc1r variants consisting of 5 nonsynonymous sites (Val60Leu, Arg67Gln, Val92Met, Arg163Gln and Ala299Val) and 2 synonymous sites (C414T and A942G), among which C414T and Ala299Val were reported for the first time. Confirmation and analysis were also made of 122 individuals at three common point mutations (Val92Met, Arg163Gln, A942G) using PCR-SSCP. The frequency of Arg163Gln variant varies in the four ethnic populations, with percentage of 40%, 85.0%, 66.2% and 72.7%, respectively, while those of Val92Met and A942G are roughly similar in these four populations. The different environments, migration and admixture of various ethnic groups in China might have impact on the observed frequency of Arg163Gln.