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.