BBB seminar: Anders Molven
The doctor who never gave up: A large Norwegian family with malignant melanoma and mutation in the cell cycle gene CDK4
Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital
Malignant melanoma is the most aggressive form of skin cancer and its prevalence has increased considerably during the last four decades. The tumors are characterized by CDKN2A (p16) alterations and mutations in the MAP-kinase pathway. Sun exposure is the major risk factor, but genetic predisposition also plays a role in the development of malignant melanoma.
Germ line mutations in two genes encoding cell cycle regulatory proteins are known to cause inherited malignant melanoma. About 20% of melanoma-prone families bear a mutation in the CDKN2A locus. Mutations in the other locus, CDK4, are much rarer. In the 1960s, Dr. Magne Grimstvedt identified a large family from the Haugesund region with multiple atypical nevi and malignant melanomas. Subsequently, six generations and more than one hundred family members were traced and 20 cases of melanomas verified. We have found that CDK4 codon 24 is mutated from CGT to CAT (Arg24His) in this unusually large melanoma kindred. The mutation is identical to that of 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 of 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 selection pressure, this observation may be explained by the CG dinucleotide of codon 24 representing a mutational hotspot in the CDK4 gene.