Deregulation of E2F family member activities occurs due to the functional deviation of the upstream molecules in this pathway, which includes inactivation of Rb pocket proteins (pRb, p107, p130), p16INK4a tumor suppressive functions, genetic manipulation of cyclin D (D1, D2 and D3) oncogenes and its kinase partners CDK4/6, which confers a growth advantage and thus has become a hallmark of human cancer [72], [73]. The gene discussed is CDKN2A; the disease is cancer.