A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families

Abstract

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 p16INK4a , 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 p16INK4a 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.

A CDKN2A Mutation in Familial Melanoma that Abrogates Binding of p16INK4a to CDK4 but not CDK6

“…These analyses were made possible by the identification of an individual who is homozygous for the mutation. Such situations are very rare, and to date we are only aware of two other examples (34,35), and an even more remarkable case with distinct alterations in each INK4a allele (26). Characterization of primary dermal fibroblasts from two of these Figure 5.…”

Functional, structural, and genetic evaluation of 20CDKN2Agerm line mutations identified in melanoma-prone families or patients

“…INK4A mutants to bind to CDK4 in an in vitro coimmunoprecipitation assay. Four previously documented loss of function mutants were employed as positive controls, as well as two founder missense mutations: Arg24Pro [Harland et al, 1997;Ghiorzo et al, 2004], Val59Gly [Yakobson et al, 2003], Ala68Leu [Rizos et al, 2001a], Asn71Ser [Reymond and Brent, 1995;Ruas and Peters, 1998;Ranade et al, 1995;Della Torre et al, 2001], p.Met53Ile, and p.Gly101Trp. Consistent with published findings, these variants showed an impaired capacity to bind CDK4, estimated at 2%, 20%, 3%, 48%, 0%, and 56.5%, respectively, relative to WT p16 INK4A ( Fig.…”

Clinical genetic testing for familial melanoma in Italy: A cooperative study

“…Most CDKN2A mutations are missense mutations located in the coding sequences of exons 1a and 2, and many seem to derive from ancestral founders. [2][3][4][5][6][7][8][9][10][11] CDKN2A mutations have been found in 20% to 40% of melanoma families with 3 or more affected members. 1 However, the proportion of families with mutations varies between countries, depending on factors such as baseline melanoma incidence rates and family and population selection in studies.…”