Loss of p16INK4 protein, alone and together with loss of retinoblastoma protein, correlate with hepatocellular carcinoma progression

To investigate the role of p16INK4 protein absence in hepatocellular carcinoma progression, we examined p16INK4 expression immunohistochemically in 81 primary and 23 metastatic lesions of hepatocellular carcinoma, in which retinoblastoma protein status had been determined. p16INK4 protein was absent from 44% of the total of 104 tumors. The rate of p16INK4 absence was twice as high in metastatic lesions (74%) compared with primary lesions (36%) (P=0.001). Loss of p16INK4 and/or retinoblastoma protein was significantly associated with decreased tumor differentiation, vascular invasion and metastasis. In conclusion, p16INK4 protein absence, alone and together with loss of retinoblastoma protein, contributes to hepatocellular carcinoma progression.