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 hepatocel lular carcinoma (HCC), We have analyzed the status of the p16(INK4)(MT S1) gene, a cyclin-dependent kinase inhibitor, in 26 patients with HCC of different etiologies, Four patients carried hemizygous germ-line p oint mutations of the p16(INK4)(MTS1) gene, suggesting the existence o f familial HCC involving this gene, The wild-type allele was lost in t he tumor in 2 of these 4 patients, Three of the patients carrying a ge rm-line mutation had non-cirrhosis-associated HCC. No somatic mutation s of p16(INK4)(MTS1) were observed in the 26 cases of HCC. The most co mmon 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.