Deletion of the p16 locus is the most frequent copy number alteration across 12 commonly occurring cancers types, and p16 is among the genes most frequently silenced by methylation.1 In contrast, Rb1 mutations are only frequently detected in retinoblastoma and small cell lung cancer (SCLC).4, 5 The markedly increased frequency of p16 as compared to RB1 loss in human cancers suggests that p16 has critical tumor suppressive functions that are not mediated through RB1. This evidence concerns the gene RB1 and retinoblastoma.