Association Found Between MC1R Variant and Melanoma Risk

A new study finds that melanocortin-1 receptor (MC1R) is a risk factor for melanoma independent of sun exposure, supporting recent mouse model research that showed a UV radiation (UVR)-independent pathway for development of melanoma and highlighting the importance of the genetic background of the host.

Judith Wendt, MD, PhD, Medical University of Vienna (Vienna, Austria) and coauthors have reported on their hospital-based case-control study that included genetic testing, questionnaires, and other data among 991 patients with melanoma and 800 control patients. Compared with wild-type carriers, carriers of MC1R variants were at higher melanoma risk after statistically adjusting for previous UVR exposure (represented by prior sunburns and signs of actinic skin damage identified by dermatologists), age, and sex. The findings suggest that carriers of certain MC1R variants were at higher risk of melanoma independent of their sun exposure history.

Endogenous risk factors have been accepted as contributing to the risk of developing melanoma in collaboration with exogenous factors such as intermittent sun exposure leading to sunburns in childhood and adolescence. However, as the UV radiation (UVR) dependency of melanoma is not as clear or linear as in squamous cell carcinoma, the effect of pigmentation variants on melanoma development has become more important in evaluation of melanoma risk factors. The most important gene affecting pigmentation, which determines each individual’s phenotype (and melanoma risk), is the MC1R. Some variants in this highly polymorphic gene lead to a change of receptor function and subsequently to altered receptor signaling, thereby influencing the ratio of eumelanin (brown to black, photoprotective, stable) to pheomelanin (yellow to red, less photoprotective, generates reactive oxygen species (ROS) and subsequent DNA damage).

Researchers have suggested that carriers of specific MC1R variants that lead to a higher pheomelanin/ eumelanin are more likely to be at higher risk for melanoma. The study aimed to test this hypothesis in a human case-control setting by performing multivariate analyses. The findings showed that carrying 2 or more MC1R variants was associated with a significant 2-fold increased risk of melanoma compared with wild-type carriers after statistically controlling for past sun exposure. "Further studies are required to better elucidate the molecular mechanisms underlying melanoma development under altered MC1R function," the authors concluded.

The study, by Wendt J et al, was published April 6, 2016, in the journal JAMA Dermatology.

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