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Does MC1R genotype convey information about melanoma risk beyond risk phenotypes?

ABSTRACT: A study was carried out to describe associations of MC1R variants and melanoma in a US population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure measures.Melanoma patients (n = 960) and controls (n = 396) self-reported phenotypic characteristics and sun exposure via structured questionnaire and underwent a skin examination. Logistic regression was used to estimate associations of high- and low-risk MC1R variants and melanoma, overall and within phenotypic and sun exposure strata. A meta-analysis of results from published studies was undertaken.Carriage of 2 low-risk or any high-risk MC1R variants was associated with increased risk of melanoma (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.0-2.8; and OR, 2.2; 95% CI, 1.5-3.0, respectively). However, risk was stronger in or limited to individuals with protective phenotypes and limited sun exposure, such as those who tanned well after repeated sun exposure (OR, 2.4; 95% CI, 1.6-3.6), had dark hair (OR, 2.4; 95% CI, 1.5-3.6), or had dark eyes (OR, 3.2; 95% CI, 1.8-5.9). We noted this same pattern of increased melanoma risk among persons who did not freckle, tanned after exposure to first strong summer sun, reported little or average recreational or occupational sun exposure, or reported no sun burning events. Meta-analysis of published literature supported these findings.These data indicate that MC1R genotypes provide information about melanoma risk in those individuals who would not be identified as high risk based on their phenotypes or exposures alone.

SUBMITTER: Kanetsky PA

PROVIDER: S-EPMC2864335 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Does MC1R genotype convey information about melanoma risk beyond risk phenotypes?

Kanetsky Peter A PA Panossian Saarene S Elder David E DE Guerry DuPont D Ming Michael E ME Schuchter Lynn L Rebbeck Timothy R TR

Cancer 20100501 10

<h4>Background</h4>A study was carried out to describe associations of MC1R variants and melanoma in a US population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure measures.<h4>Methods</h4>Melanoma patients (n = 960) and controls (n = 396) self-reported phenotypic characteristics and sun exposure via structured questionnaire and underwent a skin examination. Logistic regression was used to estimate associations of high- and low-risk MC1R vari ...[more]

PMID: 20301115

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Project description:BackgroundCarrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.MethodsWe included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ?2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.ResultsCarrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ? P ? .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ? P ? .04), hair color (.006 ? P ? .06), and number of nevi (6.9 × 10(-6) ? P ? .02).ConclusionResults show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

Project description:BackgroundSeveral algorithms are available for the dermoscopic diagnosis of pigmented skin lesions. The MC1R gene is a key determinant of pigmentation characteristics that are established host-related melanoma risk factors.ObjectivesTo investigate the association of dermoscopic features of sporadic cutaneous melanomas with clinical characteristics of patients and corresponding tumours and with genetic changes in the MC1R and BRAF genes.MethodsA total of 64 dermoscopic images of 62 patients were scored by ABCD rule and modified pattern analysis. Detailed patients' and melanomas' characteristics were collected. Patients were screened for germline MC1R variants and related melanomas for somatic V600 BRAF mutations.ResultsA lower total dermoscopic score (TDS) was observed in melanomas of patients with red hair (P = 0.019), due to reduced dermoscopic structures (P < 0.0001). Thicker melanomas showed higher TDS values (P = 0.021) due to sharper borders (P < 0.0001) and higher number of colors (P = 0.004). An atypical pigment network was prevalent in superficial spreading melanomas (P = 0.010), in individuals with dark skin (P = 0.043) and hair color (P = 0.001). An atypical vascular pattern was more frequent in nodular (P < 0.0001) and thick (P < 0.0001) melanomas, in individuals with skin type I-II (P = 0.037), blond or red hair color (P = 0.032) and blue or green eyes (P = 0.014). Melanomas of MC1R R carriers showed lower TDS value (P = 0.037), reduced dermoscopic structures (P = 0.001) and lower prevalence of atypical pigment network (P = 0.001). No differences were identified between BRAF-mutated or wild-type melanomas.ConclusionsWe suggest a phenotypic/MC1R profile for melanoma patients and their tumours. Melanomas of MC1R R carriers show a significant lower TDS value, with reduced dermoscopic structures, and a lower prevalence of an atypical pigment network. Non-carriers of MC1R R variants develop melanomas dermoscopically characterized by an atypical pigment network which is prevalent in superficial spreading melanomas, in patients with dark complexion and less frequent in red-haired individuals.

Project description:BackgroundMelanocortin-1 receptor (MC1R) gene variants are very common and are associated with melanoma risk, but their contribution to melanoma risk prediction compared with traditional risk factors is unknown. We aimed to 1) evaluate the separate and incremental contribution of MC1R genotype to prediction of early-onset melanoma, and compare this with the contributions of physician-measured and self-reported traditional risk factors, and 2) develop risk prediction models that include MC1R, and externally validate these models using an independent dataset from a genetically similar melanoma population.MethodsUsing data from an Australian population-based, case-control-family study, we included 413 case and 263 control participants with sequenced MC1R genotype, clinical skin examination and detailed questionnaire. We used unconditional logistic regression to estimate predicted probabilities of melanoma. Results were externally validated using data from a similar study in England.ResultsWhen added to a base multivariate model containing only demographic factors, MC1R genotype improved the area under the receiver operating characteristic curve (AUC) by 6% (from 0.67 to 0.73; P?<?0.001) and improved the quartile classification by a net 26% of participants. In a more extensive multivariate model, the factors that contributed significantly to the AUC were MC1R genotype, number of nevi and previous non-melanoma skin cancer; the AUC was 0.78 (95% CI 0.75-0.82) for the model with self-reported nevi and 0.83 (95% CI 0.80-0.86) for the model with physician-counted nevi. Factors that did not further contribute were sun and sunbed exposure and pigmentation characteristics. Adding MC1R to a model containing pigmentation characteristics and other self-reported risk factors increased the AUC by 2.1% (P?=?0.01) and improved the quartile classification by a net 10% (95% CI 1-18%, P = 0.03).ConclusionsAlthough MC1R genotype is strongly associated with skin and hair phenotype, it was a better predictor of early-onset melanoma than was pigmentation characteristics. Physician-measured nevi and previous non-melanoma skin cancer were also strong predictors. There might be modest benefit to measuring MC1R genotype for risk prediction even if information about traditional self-reported or clinically measured pigmentation characteristics and nevi is already available.

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Does MC1R genotype convey information about melanoma risk beyond risk phenotypes?

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Does MC1R genotype convey information about melanoma risk beyond risk phenotypes?

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