Melanocortin-1 receptor (MC1R) genotypes do not correlate with size in two cohorts of medium-to-giant congenital melanocytic nevi

Congenital melanocytic nevi (CMN) are cutaneous malformations whose prevalence is inversely correlated with projected adult size. CMN are caused by somatic mutations, but epidemiological studies suggest that germline genetic factors may influence CMN development. In CMN patients from the U.K., genetic variants in the MC1R gene, such as p.V92M and loss-of-function variants, have been previously associated with larger CMN. We analyzed the association of MC1R variants with CMN characteristics in 113 medium-to-giant CMN patients from Spain and from a distinct cohort of 53 patients from France, Norway, Canada and the U.S. These cohorts were similar at the clinical and phenotypical level, except for the number of nevi per patient. We found that the p.V92M or loss-of-function MC1R variants either alone or in combination did not correlate with CMN size, in contrast to the U.K. CMN patients. An additional case-control analysis with 259 unaffected Spanish individuals, showed a higher frequency of MC1R compound heterozygous or homozygous variant genotypes in Spanish CMN patients compared to the control population (15.9% vs. 9.3%; P=0.075). Altogether, this study suggests that MC1R variants are not associated with CMN size in these non-U.K. cohorts. Additional studies are required to define the potential role of MC1R as a risk factor in CMN development. SIGNIFICANCECongenital melanocytic nevi (CMN) are common pigmented lesions that originate during prenatal life, without clear evidence of a genetic predisposition. To date, limited data exist regarding the role of the MC1R gene, a key regulator of human pigmentation, in the development of the class of rarer CMN that are greater than 10 cm diameter at projected adult size and associated with increased morbidity or mortality risks. This study provides data from a large set of such CMN patients to support the hypothesis that MC1R could be involved in the development of these types of lesions, but at the same time discounting its influence on the size of CMN across distinct populations. Improving our understanding of genetic susceptibility to rare types of CMN is necessary to determine whether routine germline genotyping is relevant in clinical practice.