Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the lung, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. The D84V mutant is predicted to confer loss of function to the CDKN2A protein as demonstrated by an inability to bind and inhibit the cyclin-dependent kinases CDK4 and CDK6. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.