CDKN2A encodes two tumor suppressor proteins, p16INK4A and p14ARF, that negatively regulate cell proliferation by inhibiting CDK4/6 kinases and preventing their interaction with cyclins D and phosphorylation of retinoblastoma protein 1. Beyond cell cycle control, CDKN2A participates in cellular senescence regulation, with p16INK4A expression serving as a senescence marker associated with replicative senescence and age-related pathologies 2. Germline CDKN2A mutations are responsible for the majority of hereditary melanoma cases, with characteristic loss conferring increased melanoma susceptibility 34. CDKN2A loss is a frequent event driving melanoma progression and is diagnostically important in mesothelioma, where homozygous deletion detected by FISH aids in diagnosis 51. Loss of CDKN2A expression occurs across multiple cancer types and correlates with poor survival in certain malignancies, with aberrant expression linked to cell cycle deregulation, p53 signaling, and immune infiltration 6. Deleterious mutations in p14ARF can alter protein stability and disrupt protein-protein interactions, compromising multiple signaling cascades and contributing to cancer development 7. Therapeutically, CDK4/6 inhibition targeting p16 substrates represents a primary strategy for precision medicine in CDKN2A-deficient melanomas 1.