GERMLINE MUTATIONS OF THE CDKN2 GENE IN UK MELANOMA FAMILIES

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cy clin D kinase inhibitor p16, and more rarely, mutations in the gene co ding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and a nalysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in C DKN2 were found in six families. Three of the mutations (Met53Ile, Arg 24Pro and 23ins24) have been reported previously, We have identified t wo novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segr egation with the disease and their likely functional effect on the CDK N2 protein, In binding assays the protein expressed from the previousl y described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Th r appeared to be functional in this assay. Arg24Pro appeared to bind t o CDK6, but not to CDK4, No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon, The penet rance of these mutant CDKN2 genes is not yet established, nor is the r isk of non-melanoma cancer to gene carriers.