Alteration of the p14ARF gene and p53 status in human hepatocellular carcinomas

Background The INK4a/ARF locus encodes p16^INK4a and p14^ARF, both of which are crucial for two tumor suppressor pathways, retinoblastoma (RB)/p16^INK4a and p53/ARF. Inactivation of RB/p16^INK4a was frequently reported, but alterations of the p14^ARF gene in hepatocellular carcinoma (HCC) in the Japanese population have been insufficiently analyzed.Methods To determine the role of p53/ARF alteration in hepatocarcinogenesis, we examined 44 HCCs for mRNA expression, deletion, mutation, and promoter hypermethylation of the p14^ARF gene; alterations of p53 were also analyzed in the same series of HCCs.Results Homozygous deletion, spanning from exon 1 to exon 2, was found in 1 HCC mutations within exon 2 were found in 2 HCCs, but no promoter hypermethylation was detected. All 3 HCCs with p14^ARF alteration were well differentiated. Twelve of the 44 HCCs (27.2%) showed immunohistochemical evidence of p53 alteration; however, only 1 of the tumors with p53 alteration was well differentiated. TaqMan polymarase chain reaction (PCR) indicated that the expression of p14^ARF in HCCs was higher than in that in all but three of the corresponding non-tumorous tissues (P < 0.0001), and increased expression of p14^ARF seemed to be associated with poorly differentiated phenotype. Absence of p14^ARF expression was seen in only one HCC, with homozygous deletion of the p14^ARF gene.Conclusions Compared with p53 alteration, p14^ARF alteration does not occur frequently, but may play a role in a subset of Japanese HCCs in the early stage of hepatocarcinogenesis. On the other hand, overexpression of p14^ARF was frequently observed in HCC, especially in poorly differentiated tumors, probably reflecting oncogenic stimuli in these tumors.