Assessing MC1R Variants in Lentigo Maligna Melanoma within the Utah Population

Abstract

Lentigo maligna (LM) and lentigo maligna melanoma (LMM) arise from chronically sun-damaged skin. LM/LMM incidence continues to increase, particularly in Utah, where melanoma rates are twice the national average. The melanocortin-1 receptor (MC1R) has been studied in melanocyte pigmentation and DNA repair but has yet to be thoroughly investigated in LM/LMM. We investigated allele and genotype frequencies of germline MC1R variants among 175 Utah patients diagnosed with LM/LMM and 402 Utah reference individuals. The comparative analysis demonstrated an increased frequency of the D294H allele (0.046; P = 0.0042) and a decreased frequency of the V60L allele (0.074; P = 0.034) in patients with LM/LMM. The LM/LMM group demonstrated a higher OR compared with the Utah reference group associated with R151C homozygosity compared with heterozygous R151C [OR = 5.6; 95% confidence interval (CI), 0.98-32; P = 0.052] and R151C homozygosity compared with wild type (OR = 5.7; 95% CI, 1.1-30; P = 0.042). D294H heterozygosity was strongly associated with LM/LMM (OR = 3.8; 95% CI, 1.3-11; P = 0.014). Conversely, V60L heterozygosity was less strongly associated with LM/LMM (OR = 0.52; 95% CI, 0.26-1.1; P = 0.072). Stratified analyses showed no significant differences in age or gender across the key MC1R variants studied. These data highlight significant differences in MC1R allele frequencies in patients with LM/LMM, demonstrating that D294H is associated with increased LM/LMM risk, whereas the V60L variant is inversely associated with risk. This study provides the first comprehensive analysis of specific high-risk MC1R variants in patients with LM/LMM in Utah.

Significance: Our study is the first comprehensive analysis of MC1R germline variants in patients with LM/LMM in Utah, a region with an exceptionally high melanoma incidence. We draw new risk associations in LM/LMM, identifying an increased risk with the D294H and R151C variants. We also describe a novel inverse association for V60L, warranting further investigation. This study contributes to improved targeted risk stratification and an increased understanding of an understudied melanoma subtype.

Figure 1

MC1R variant allele frequencies vary between the Utah reference group and LM/LMM cohorts. A, Bar graph of MC1R allele frequencies in different populations derived from the dSNP database, N = 24,662–123,831. B, Bar graph comparing the European dbSNP data (N = 18,644–111,821) with the Utah reference group (N = 402). C, Bar graph comparing the European dbSNP data (N = 18,644–111,821) with the LM/LMM cohort (N = 175). D, Bar graph comparing the MC1R allele frequencies between the LM/LMM cohort (N = 175) and the Utah reference group (N = 402). Significance in B–D was assessed using Fisher’s exact test, with a P value < 0.05 considered statistically significant. P value significance thresholds: <0.05 (*), <0.01 (**), and <0.001 (***).

Figure 2

Specific MC1R genotypes confer an increased risk of developing LM/LMM. The heatmaps display the percentage frequencies of MC1R genotypes within two cohorts: (A) Mohs LM/LMM cohort and (B) the Utah reference group. The heatmaps are color-coded to reflect genotype percentages, with red indicating higher frequencies and green indicating lower frequencies. This comparison highlights the differential distribution of MC1R genotypes between patients with LM/LMM and the Utah reference group. * denotes samples for which we calculated an OR compared with WT or heterozygous/homozygous genotypes.