 Polymorphisms of the p15INK4b/p16INK4a homolog were found to segregate with melanoma susceptibility in the "Xiphophorus" indicating that INK4 proteins have been involved with tumor suppression for over 350 million years.Furthermore, the older INK4-based system has been further bolstered by the evolution of the recent addition of the ARF-based anti-cancer response.INK4 proteins are cell-cycle inhibitors.