Germline mutations of the CDKN2 gene in UK melanoma families

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclinD kinase inhibitor p16, and more rarely, mutations in the gene coding forCDK4, the protein to which p16 binds, underlie susceptibility in somemelanoma families. We have sequenced all exons of CDKN2 and analysed theCDK4 gene for mutations in 27 UK families showing evidence ofpredisposition to melanoma. Five different germline mutations in CDKN2 werefound in six families. Three of the mutations (Met53Ile, Arg24Pro and23ins24) have been reported previously. We have identified two novel CDKN2mutations (88delG and Ala118Thr) which are likely to be associated with thedevelopment of melanoma, because of their co-segregation with the diseaseand their likely functional effect on the CDKN2 protein. In binding assaysthe protein expressed from the previously described mutation, Met53Ile, didnot bind to CDK4/CDK6, confirming its role as a causal mutation in thedevelopment of melanoma. Ala118Thr appeared to be functional in this assay.Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations weredetected in exon 2 of CDK4, suggesting that causal mutations in this geneare uncommon. The penetrance of these mutant CDKN2 genes is not yetestablished, nor is the risk of non-melanoma cancer to gene carriers.