Germline mutations in the p16INK4a 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) protein¹. 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^6–12. In this report, we describe an Arg24Cys mutation in CDK4 in two unrelated melanoma families which do not carry germline p16^INK4a mutations6. 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 lymphocytes¹³. 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 kinase¹³. 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^14,15 and MEN2B¹⁶.