Melanoma development in relation to nonfunctional p16/INK4A protein and dysplastic naevus syndrome in Swedish melanoma kindreds

The CDKN2A gene encodes the cell cycle inhibitor p16/INK4A, which is involv ed in familial cutaneous melanoma. We have studied five Swedish familial me lanoma kindreds characterized by germline mutations in CDKN2A and dysplasti c naevus syndrome (DNS). We found significant correlations between germline CDKN2A mutations and melanoma and between DNS phenotype end melanoma, resp ectively. There was also a correlation between mutation status and the pres ence of DNS. In CDKN2A mutation carriers, all cases of early-onset melanoma occurred in DNS individuals, and the mean age at melanoma diagnosis was si gnificantly lower in individuals with DNS than in those without a confirmed DNS phenotype. In one family where the proband had a P48L mutation in CDKN 2A exon 1, the DNS phenotype was studied in detail. In vitro binding experi ments established that the P48L mutant protein does not bind to cdk4 or cdk 6 and thus is functionally abnormal. Furthermore, we demonstrated loss of h eterozygosity at markers on chromosome 9p flanking the CDKN2A locus in a pr imary melanoma and a metastasis from the proband. Our results are consisten t with the hypothesis that germline CDKN2A mutations and DNS both contribut e to the predisposition to melanoma and may lead to the development of earl y-onset melanoma when present in the same individual. (C) 1999 Lippincott W illiams & Wilkins.