Germline mutations in the p16(INK4a) binding domain of CDK4 in familial melanoma

Protein complexes consisting of a cyclin-dependent kinase (CDK4 or CDK6) and cyclin D control passage through the G1 checkpoint of the cell cycle by phosphorylating the retinoblastoma (RB) protein. The ability of these complexes to phosphorylate RB is inhibited by a family of low molecular weight proteins including p16(INK4a) (refs 2,3), p15(INK4B) (ref. 4), and p18 (ref. 5). Germline mutations in the p16(INK4a) gene have been identified in approximately half of families with hereditary melanoma. In this report, we describe an Arg24Cys mutation in CDK4 in two unrelated melanoma families which do not carry germline p16(INK4a) mutations. This mutation was detected in 11/11 melanoma patients, 2/17 unaffecteds and 0/5 spouses. The CDK4- Arg24Cys substitution has previously been identified as a somatic mutation in a melanoma that gives rise to a tumour-specific antigen recognized by autologous cytolytic T lymphocytes. This mutation has a specific effect on the p16(INK4a) binding domain of CDK4, but has no effect on its ability to bind cyclin D and form a functional kinase. Therefore, the germline Arg24Cys mutation in CDK4 generates a dominant oncogene that is resistant to normal physiological inhibition by p16(INK4a). The only previous example of a dominant oncogene transmitted in the human germline is the RET gene that gives rise to MEN2A and MEN2B.