However, the Rb gene is infrequently mutated or deleted, instead upstream pathways that regulate Rb by phosphorylation on Cdk sites are altered in the majority of human cancers, including deletion and mutation of the p16 tumor suppressor and upregulation and mutation of cyclin D1, D2, D3, Cdk4 and Cdk6 genes (Sherr and McCormick, 2002; Knudsen and Knudsen, 2006; Burkhart and Sage, 2008; Henley and Dick, 2012; Choi and Anders, 2013). The gene discussed is RB1; the disease is cancer.