Mutation seen in malignant melanoma is

CDKN2A is a complex locus that encodes three different tumor sup- pressors, p15/INK4b, p16/INK4a, and p14/ARF. Of these, loss of p16/INK4a is clearly implicated in human melanoma, and experimental evidence also suppos a role for loss of p14/ARF. As already mentioned, p16/ INK4a inhibits cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), thus reinforcing the ability of the RB tumor suppressor to block cells in the G1 phase of the cell cycle. By contrast, p14/ARF enhances the activity of the p53 tumor suppressor by inhibiting MDM2, an oncoprotein that stimulates p53 degradation. CDKN2A is mutated in approximately 10% of sporadic melanomas, and these mutations uniformly abolish the production of p16/INK4a and more variably affect p14/ ARF. However, it is suspected that these mutations are the tip of the "oncogenic iceberg" with respect to molec- ular lesions affecting the G1 checkpoint. For example, 30% to 70% of melanomas show loss of p16/INK4a expression though varied mechanisms, and other famil- ial and sporadic melanomas have mutations in CDK4