MC1R variants predisposing to concomitant primary cutaneous melanoma in a monozygotic twin pair

Abstract

BackgroundConcomitant primary cutaneous melanoma in monozygotic twins has been reported in only two pairs but in neither of them genetic analysis was performed. Two high-penetrance susceptibility genes, CDKN2A and CDK4 and one low-penetrance gene, MC1R, are well-defined genetic risk factors for melanoma. MITF has been recently identified as a novel intermediate risk melanoma-predisposing gene.Case presentationWe describe the extraordinary occurrence of a primary cutaneous invasive melanoma in two 44-year-old identical, female twins, on the same body site within 30 days of each other and report for the first time the genetic analysis of melanoma susceptibility genes in both twins. Data on characteristics of the twins were collected through a standardized questionnaire and skin examination. Exons 1α, 1β, 2 and 3 of CDKN2A, exon 2 of CDK4, the entire open reading frame of MC1R and the recently described MITF c.952 G > A (p.Glu318Lys) variant were investigated by direct sequencing. Sequencing analysis of the high-penetrance susceptibility genes showed no changes in CDKN2A and in exon 2 of the CDK4 gene. Both patients were heterozygous for the same CDKN2A UTR c.*29C > G variant. Interestingly, the same two heterozygous variants of the MC1R were identified in both twins: the c.451C > T (p.Arg151Cys) and the c.456C > A (p.Tyr152*) variants. Neither patient showed the c.952 G > A (p.Glu318Lys) substitution in the MITF gene.ConclusionsIdentification 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.

Dermoscopic features of cutaneous melanoma are associated with clinical characteristics of patients and tumours and with MC1R genotype

“…A germline homozygous MC1R R151C variant was detected in a woman with skin type I, red hair and ‘white’ dysplastic nevi who developed two amelanotic melanomas . We recently reported the occurrence of concomitant primary hypomelanotic melanoma on the same body site in a pair of red‐haired monozygotic twins, heterozygous for two MC1R R variants . In the present series, four patients presented a hypo/amelanotic melanoma and all carried at least one R variant in the MC1R genotype two being homozygous for R variants (R151C/R160W and R142H/R151C), one heterozygous R / r (R151C/V60L) and one R /wt (R160W/wt).…”

“…The association of MC1R RHC variants and melanomas lacking significant pigmentation has been described in two case reports . A germline homozygous MC1R R151C variant was detected in a woman with skin type I, red hair and ‘white’ dysplastic nevi who developed two amelanotic melanomas .…”

“…26,30 The association of MC1R RHC variants and melanomas lacking significant pigmentation has been described in two case reports. 31,32 A germline homozygous MC1R R151C variant was detected in a woman with skin type I, red hair and 'white' dysplastic nevi who developed two amelanotic melanomas. 31 We recently reported the occurrence of concomitant primary hypomelanotic melanoma on the same body site in a pair of red-haired monozygotic twins, heterozygous for two MC1R R variants.…”

Estudo da diversidade dos genes MC1R e SLC24A5 em populações globais: avaliação de aspectos evolutivos e ambientais

“…Outros estudos também identificaram diversas variantes do MC1R relacionadas com susceptibilidade ao melanoma (Ghiorzo et al, 2012;Pellegrini et al, 2012). A compreensão da expressão e regulação deste receptor é essencial para que se compreenda seus efeitos sobre a melanogênese e o risco de melanoma (Swope et al, 2012 …”

“…Other studies have also identified several MC1R coding variants related to melanoma susceptibility (Ghiorzo et al, 2012;Pellegrini et al, 2012). Understanding the expression and activity regulation of this receptor is essential to comprehend its effects on melanogenesis and melanoma risk (Swope et al, 2012).…”