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Original Investigation |

Human Determinants and the Role of Melanocortin-1 Receptor Variants in Melanoma Risk Independent of UV Radiation Exposure

Judith Wendt, MD, PhD1; Sabine Rauscher, MSc1; Sebastian Burgstaller-Muehlbacher, PhD1,2; Ingrid Fae, MSc3; Gottfried Fischer, MD3; Hubert Pehamberger, MD1; Ichiro Okamoto, MD1
[+] Author Affiliations
1Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria
2Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California
3Division of Blood Group Serology, Department of Transfusion Medicine, Medical University of Vienna, Vienna, Austria
JAMA Dermatol. 2016;152(7):776-782. doi:10.1001/jamadermatol.2016.0050.
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Importance  Despite the unquestioned relationship of UV radiation (UVR) exposure and melanoma development, UVR-independent development of melanoma has only recently been described in mice. These findings in mice highlight the importance of the genetic background of the host and could be relevant for preventive measures in humans.

Objective  To study the role of the melanocortin-1 receptor (MC1R) and melanoma risk independently from UVR in a clinical setting.

Design, Setting, and Participants  Hospital-based case-control study, including genetic testing, questionnaires, and physical data (Molecular Markers of Melanoma Study data set) including 991 melanoma patients (cases) and 800 controls.

Main Outcomes and Measures  Association of MC1R variants and melanoma risk independent from sun exposure variables.

Results  The 1791 participants included 991 with a diagnosis of melanoma and 800 control patients (mean [SD] age, 59.2 [15.6] years; 50.5% male). 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 compared with wild-type carriers (≥2 variants, OR, 2.13 [95% CI, 1.66-2.75], P < .001; P for trend <.001). After adjustment for sex, age, sunburns in the past, and signs of actinic skin damage, the associations remained significant (OR, 1.65 [95% CI, 1.02-2.67] for R/R, OR, 2.63 [95% CI, 1.82-3.81] for R/r; OR, 1.83 [95% CI, 1.36-2.48] for R/0; and OR, 1.50 [95% CI, 1.01-2.21] for r/r, with P values ranging from <.001 to .04 when adjusted for facial actinic skin damage; OR, 2.36 [95% CI, 1.62-3.43] for R/r; and OR, 1.47 [95% CI, 1.08-1.99] for R/0 with P values ranging from <.001 to .01 when adjusted for dorsal actinic skin damage; and OR, 2.54 [95% CI, 1.76-3.67] for R/r, OR, 1.75 [95% CI, 1.30-2.36] for R/0; and OR, 1.50 [95% CI, 1.02-2.20] for r/r with P values ranging from <.001 to .04 when adjusted for actinic skin damage on the hands).

Conclusions and Relevance  Carriers of MC1R variants were at increased melanoma risk independent of their sun exposure. Further studies are required to elucidate the causes of melanoma development in these individuals.

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