CDKN2B and retinoblastoma: In human HCC, retinoblastoma pathway alterations (p16INK4a, p15INK4b or RB1 genes) – i.e. mutation/deletion of RB1 and/or methylation of p16INK4a, p15INK4b promoters - are observed in more than 80% of cases, with repression of p16INK4a by promoter methylation being the most frequent alteration [43], as well as gankyrin expression [39], indicating that the pRb checkpoint is dysfunctional in the vast majority of human HCCs.