The occurrence of melanoma concordant for site and age of onset in monozygotic twins has been reported in only two pairs but in neither of them genetic analysis was performed. St-Arneault et al.  described two identical male twins (from a set of triplets) who developed melanoma at age 53, at the same site and within a time frame of 2 months, while the fraternal triplet showed no evidence of tumour. More recently, Rao et al. reported two 71-year-old, identical female twins, diagnosed with melanoma at the same time (within 10 days of each other) and location (right calf). Our patients were skin type 1 as the latter pair but they were younger than both pairs.
Studies in twin pairs are of great interest to estimate the relative effect of genetic and environmental influences on melanoma development. In a recent large population-based study of Australian twins, genetic influences were shown to be a significant source of variation in liability to melanoma with identical twins being more than four times more likely to be affected with melanoma if they had an affected co-twin than non-identical twins .
MC1R variants have been associated with a 1.2 to 2.4-fold increased risk of melanoma with an additive effect for multiple variants [10–12]. A double variation in the MC1R gene, the c.451C > T (p.Arg151Cys) and the c.456C > A (p.Tyr152*), was detected in our twins. The p.Arg151Cys has been shown to confer the highest melanoma risk with summary estimates ranging from 1.78 (95%CI 1.45–2.20) to 1.93 (95%CI 1.54–2.41) in two recent meta-analyses [10, 11]. We previously reported a significant association of the p.Arg151Cys allele with melanoma risk in a population from central Italy, with an OR of 2.94 (95%CI, 1.04–8.31) . In functional studies, the p.Arg151Cys mutant receptor showed a reduced cell surface expression with intracellular retention and a corresponding impairment in cAMP coupling . The nonsense p.Tyr152* is a rare RHC variant associated with a severe functional impairment of the MC1R due to the lack of the last four transmembrane fragments [14, 15]. Interestingly, MC1R-associated melanoma risk has been shown to increase with the number of variants in the genotype supporting the MC1R-associated susceptibility in our patients carrying two nonfunctional MC1R variants. Finally, carriers of MC1R RHC variants have been recently suggested to develop melanomas lacking significant pigmentation [16, 17] as also observed in the hypomelanotic melanomas of our twins.
In addition to the well-defined association of MC1R with melanoma, other low-penetrance melanoma risk alleles have been described in genes related to pigmentation, nevus count, immune responses, DNA repair, metabolism and the vitamin D receptor . In this regard, we cannot rule out the possible involvement of other low-penetrance melanoma susceptibility alleles in our twins since they were not genotyped in our patients.
The concordance for cutaneous melanoma as well as the congruence for its location and identity of the age of onset in monozygotic twins support the role of genetic rather than environmental factors in the development of melanoma. Detection of two high-risk MC1R variants in our identical twins in the absence of CDKN2A and CDK4 mutations highlights the contribution of low penetrance genes, such as MC1R, in melanoma susceptibility, although additional known or as yet unknown genetic risk factors might be involved.