Germ-line mutations of thep16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma

Abstract

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. Low 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.