Germ-line mutations of the p16(INK4)(MTS1) gene occur in a subset of patients with hepatocellular carcinoma

The molecular mechanisms of hepatocarcinogenesis are poorly understood. Only very recently has there been a suggestion of familial hepatocellular carcinoma (HCC), We have analyzed the status of the p16(INK4)(MTS1) gene, a cyclin-dependent kinase inhibitor, in 26 patients with HCC of different etiologies, Four patients carried hemizygous germ-line point mutations of the p16(INK4)(MTS1) gene, suggesting the existence of familial HCC involving this gene, The wild-type allele was lost in the tumor in 2 of these 4 patients, Three of the patients carrying a germ-line mutation had non-cirrhosis-associated HCC. No somatic mutations of p16(INK4)(MTS1) were observed in the 26 cases of HCC. The most common somatic alteration of the p16(INK4)(MTS1) gene in HCC was de novo methylation, which was detected in 48% of the cases. Lour levels (21%) of p16(INK4)(MTS1) gene allele loss were observed. Altogether, these results indicate that alteration of the p16(INK4)(MTS1) gene plays an important role in the genesis of HCC.