RB1 and cancer: Considering that p53 is the most frequently mutated tumor suppressor gene in cancer [33], that p53 inactivation can also occur in the absence of p53 gene mutations (reviewed in [34]), and that alterations of Rb (reviewed in [35]) and other p16 interaction partners such as CDK4 (cyclin dependent kinase 4) [36] are also common in cancer, the high rate of p16 upregulation is not a surprise.