Germline p16^INK4A mutation and protein dysfunction in a family with inherited melanoma

The gene encoding the cell cycle inhibitor p16^INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16^INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16^INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16^INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16^INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16^INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16^INK4A gene in the development of some cases of familial melanoma.