A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation

Abstract

Mutations in two loci encoding cell-cycle-regulatory proteins have been shown to cause familial malignant melanoma. About 20% of melanoma-prone families bear a mutation in the CDKN2A locus, which encodes two unrelated proteins, p16INK4A and p14ARF. Mutations in the other locus, CDK4, are much rarer and have been linked to the disease in only three families worldwide. In the 1960s, a large Norwegian pedigree with multiple atypical nevi and malignant melanomas was identified. Subsequently, six generations and more than 100 family members were traced and 20 cases of melanoma verified. In this article, we report that CDK4 codon 24 is mutated from CGT to CAT (Arg24His) in this unusually large melanoma kindred. Intriguingly, one of the family members had ocular melanoma, but the CDK4 mutation could not be detected in archival tissue samples from this subject. Thus, the case of ocular melanoma in this family was sporadic, suggesting an etiology different from that of the skin tumors. The CDK4 mutation in the Norwegian family was identical to that in melanoma families in France, Australia, and England. Haplotype analysis using microsatellite markers flanking the CDK4 gene and single-nucleotide polymorphisms within the gene did not support the possibility that there was a common founder, but rather indicated at least two independent mutational events. All CDK4 melanoma families known to date have a substitution of amino acid 24. In addition to resulting from selection pressure, this observation may be explained by the CG dinucleotide of codon 24 representing a mutational hot spot in the CDK4 gene.

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

“…As expected, given that very few melanoma families worldwide have been reported to harbor mutations in CDK4, [28][29][30][31] and only one in Italy, 15 none of our families harbored mutations in CDK4. Conversely, 33% of the families overall carried mutations in CDKN2A.…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…Germline mutations of CDK4, an Rb-kinase that is inhibited by INK4A, have also been identified in melanoma-prone kindreds (Wolfel et al 1995;Zuo et al 1996;Soufir et al 1998;Tsao et al 1998;Molven et al 2005). These mutations, which are a rare cause of familial melanoma, target a conserved arginine residue (Arg24) and render the mutant protein insensitive to inhibition by the INK4 class of cell cycle inhibitors.…”

Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

“…The CDKN2A locus accounts for susceptibility in $25% of all melanoma families (Bishop et al, 2002), whereas mutations in the CDK4 oncogene are rare (Zuo et al, 1996;Soufir et al, 1998;Molven et al, 2005). In addition to germline changes, somatic mutations of both CDKN2A and CDK4 occur during melanoma development (Castellano et al, 1997;Whiteman et al, 1997;Monzon et al, 1998;Walker et al, 1998;Auroy et al, 2001).…”