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Background Familial melanoma, a cluster of several cases within a single family, accounts for approximately 10% of cases of melanoma. Hereditary melanoma is defined as two or more first-degree relatives having melanoma. A member of a melanoma-prone family has a 35–70-fold increased relative risk of developing a melanoma. Genetic susceptibility is linked to the major susceptibility genes CDKN2A and CDK4, and the minor susceptibility gene MC1R. Objectives To determine the clinical and genetic characteristics of cutaneous melanoma in melanoma-prone families from Uruguay. Methods We studied 13 individuals from six melanoma-prone families living in Uruguay. Phenotype, familial and personal history were recorded. Molecular screening of CDKN2A and CDK4 was done by polymerase chain reaction–single strand conformational polymorphism analysis. The MC1R gene was sequenced. Results Mutations in CDKN2A were detected in five of six families: c.−34G>T, p.G101W and p.E88X. A novel germline mutation p.E88X, associated with hereditary melanoma in two unrelated families, is described. We hypothesize that a founder effect occurred probably in the Mediterranean region. No mutations in CDK4 were detected. Six different MC1R variants, all previously reported, were present in Uruguayan families. Conclusions The overall rate of deleterious CDKN2A mutations in our familial melanoma pedigrees, even though the sample size is small, was considerably higher (83%) than the often quoted range. [ABSTRACT FROM AUTHOR]

Background: Cutaneous melanoma tumour is classified into clinicohistopathological subtypes that may be associated with different genetic and host factors. Variation in the MC1R gene is one of the main factors of risk variation in sporadic melanoma. The relationship between MC1R variants and the risk of developing a specific subtype of melanoma has not been previously explored., Objectives: To analyse whether certain MC1R variants are associated with particular melanoma subtypes with specific clinicohistopathological features., Methods: An association study was performed between MC1R gene variants and clinicopathological subtypes of primary melanoma derived from 1679 patients., Results: We detected 53 MC1R variants (11 synonymous and 42 nonsynonymous). Recurrent nonsynonymous variants were p.V60L (30·0%), p.V92M (11·7%), p.D294H (9·4%), p.R151C (8·8%), p.R160W (6·2%), p.R163Q (4·2%) p.R142H (3·3%), p.I155T (3·8%), p.V122M (1·5%) and p.D84E (1·0%). Melanoma subtypes showed differences in the total number of MC1R variants (P = 0·028) and the number of red hair colour variants (P = 0·035). Furthermore, an association between p.R163Q and lentigo maligna melanoma was detected under a dominant model of heritance (odds ratio 2·16, 95% confidence interval 1·07-4·37; P = 0·044). No association was found between p.R163Q and Fitzpatrick skin phototype, eye colour or skin colour, indicating that the association was independent of the role of MC1R in pigmentation. No association was observed between MC1R polymorphisms and other melanoma subtypes., Conclusions: Our findings suggest that certain MC1R variants could increase melanoma risk due to their impact on pathways other than pigmentation, and may therefore be linked to specific melanoma subtypes., (© 2013 British Association of Dermatologists.)

We have screened for CDKN2A germline mutations in 49 Jewish families with two or more cases of melanoma. The Val59Gly mutation, one of the three different alterations identified among these families, was also detected independently in two kindreds from France and one from Spain. The impact of the Val59Gly substitution on the function of the cyclin-dependent kinase inhibitor p16(INK4a), a product of the CDKN2A gene, was assessed by protein-protein interaction and cell proliferation assays and related to potential structural alterations predicted by molecular modeling. Seven microsatellite markers in the vicinity of the CDKN2A gene were used to determine whether the mutation in these families is identical by descent, or represents a mutational hotspot in the CDKN2A gene. Our results show that the Val59Gly substitution impairs p16(INK4a) function, and this dysfunction is consistent with structural predictions. All melanoma-affected individuals tested in the families under study harbor this mutation. Interestingly, the Israeli pedigree includes an affected individual who is homozygous for the Val59Gly mutation. A common haplotype of microsatellite markers has been demonstrated for mutation carriers in all four pedigrees. The Israeli pedigree and one of the French melanoma families are of Moroccan and Tunisian Jewish descent, respectively, and the other families originate from regions of France and Spain close to the Pyrenees. We conclude that the Val59Gly mutation is a major contributor to melanoma risk in the families under study and that it may derive from a single ancestral founder of Mediterranean (possibly Jewish) origin.