CDKN2A encodes p16 and p14ARF, which inhibit cyclin-dependent kinase 4 (CDK4) and 6 (CDK6) and regulate Tp53 activity to promote cell-cycle arrest. CDKN2A germline mutations are associated with familial atypical multiple mole melanoma. Somatic CDKN2A mutations are highest in pancreatic cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, and melanoma. Simple CDKN2A mutations are seen in about 8% of all tumors, including 18% of skin tumors and 8% of colorectal carcinomas. Early clinical evidence indicates that CDKN2A-mutant tumors may be sensitive to CDK inhibitors.