A population-based, case-control study of MC1R variants, ultraviolet light exposure, and melanoma

Reporter: Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2011

Presenter: D. Polsky
Presenter's Institution: New York University


  • It is well known that ultraviolet light (UV) exposure is associated with increased melanoma risk. In addition, several different genes have been identified as increasing the risk of developing melanoma.
  • Melanocortin-1 receptor gene (MC1R), located on chromosome 16q24 is a melanotropin receptor that is a G protein-coupled receptor which binds to a class of pituitary pepitide hormones known as the melanocortins. Melanocortins include the different forms of melanocyte-stimulating hormone (MSH). MC1R is located on melanocytes, and it functions to control the type of melanin being produced. MC1R activation causes the melanocyte to make brown or black eumelanin, rather than red or yellow phaeomelanin. People with red hair have a mutated copy of this gene.
  • There are more than 80 variants of MC1R described. In addition to pigmentation, MC1R is involved in DNA repair, including repair of oxidative stress and UV dimers.
  • Variants of MC1R are associated with increased melanoma risk, with red hair variants "R" at greater risk than non-red hair variants "r". Given that MC1R regulates skin and hair pigmentation and is involved in DNA repair following UV damage, a gene-environment interaction between MC1R variants and UV exposure may exist.
  • Few studies have looked at whether indoor (tanning bed) and outdoor UV light exposure modifies the risk of the MC1R genotypes. This study investigates the relationship between MC1R variants, melanoma risk, and the hypothesis that environmental UV exposure to add to the risk conferred by the genetic variants.


  • Genomic DNA samples from mouthwash samples of subjects enrolled in the Minnesota Skin Health Study (a population-based study of indoor tanning and melanoma risk) were obtained for analysis. There were 924 melanoma and 813 controls which were sequenced for MC1R variants using PCR.
  • There was an equal proportion of men and women and similar distribution of ages between cases and controls. The upper age limit was 59 (not surprising given that tanning is more common in younger people).
  • Odds ratios and 95% confidence intervals were calculated for each genotype with the consensus genotype as the reference. Multiple logistic regression models were used to analyze UV exposure associations with melanoma and interactions with different genotypes.


  • 73% of subjects were identified as having at least one r or R variant
  • Increased melanoma risk was associated with the r/r (OR 1.64; 1.09-2.48), R/consensus (OR 1.58;1.18-2.12), R/r (OR 2.58; 1.81-3.68), and R/R (OR 3.85; 2.37-6.24) genotypes, but not with the r/consensus genotype (OR 1.19; 0.90-1.57).
  • Total hours of sun exposure, hours of outdoor activity, and number of lifetime sunburns were each significantly associated with disease status, but were independent of genotype.
  • In terms of outdoor sun exposure, those with 5 or fewer lifetime sunburns were compared to those with more than 5 sunburns; all genotype groups had statistically significant increased risk of melanoma if they were among the more than 5 sunburns group.
  • In terms of indoor exposure, indoor tanning was stratified according to those who tanned vs. those who never tanned. The increased risk of melanoma was greatest for the R/R genotype group who also participated in indoor tanning, with an OR of 2.44 (statistically significant). Additionally, indoor tanning was also stratified according to those who had less than 10 vs. 10+ hours of indoor tanning; there was an increased risk for those with more exposure including those with the r/r genotype. Again, the highest risk was for R/R genotype group who tanned for 10+ hours at 5.26.

Authors' Conclusions

  • These data indicate that "R" and "r" MC1R variants are associated with increased melanoma risk.
  • Risk was elevated regardless of UV exposure but was highest in R/R subjects with indoor tanning exposure. This suggests that a gene- environment interact exists.

Clinical/Scientific Implications

  • Because of its role in DNA repair, mutations in the MC1R gene appears to explain, at least in part why people with fair skin, light eyes, or those who have a tendency to freckle or burn easily are all at higher risk for melanoma as they are unable to increase melanin levels in the skin in response to high exposure to UV light and therefore increase the levels of pheomelanin.
  • If a screening test were routinely available for the mutation, it is unclear if identification of a high risk group would result in clinically significant impact on the population.
  • Having said this, those individuals with the phenotype associated with the mutation should be particularly vigilant about their sun safety. Additionally, these results may be important for risk assessment in melanoma-prone families.
  • Investigation of other modifying genes, such as those identified by genome-wide association studies may clarify the complex mecha­nisms leading to familial melanoma and further facilitate reduction of environmentally-related risk for genetically high-risk individuals.


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