Mutations of p53 gene in hepatocellular-carcinoma (hcc) correlate with tumor progression and patient prognosis - a study of 138 patients with unifocal hcc.

The mutation spectrum of p53 gene and its biological significance were studied in 138 patients with unifocal primary hepatocellular carcinoma (HCC) in Taiwan. The p53 mutations were detected in 51 cases (37%); 36 (71%) were missense mutations. The others (29%) included mutations at the intron-exon junctions (5 cases), deletion or insertion (4 cases), nonsense mutations (4 cases), and silent mutations (2 cases). The mutation sites were scattered from exons 4 to 10, predominantly (75%) in exons 5, 7, and 8. Of these mutations, 72% were transversions, mostly G:C --> T:A change (46%); while only 28% were transitions. Mutation occurred at codon 249 only in 14 cases (10%), but accounted for 27% of the mutations. The p53 mutations correlated with allele loss of p53 locus (52% vs 17% p<0.02), alpha-fetoprotein elevation (45% vs 28%, p<0.04), and poorly differentiated HCC (46% vs 10%, p<0.0001). The p53 mutation rate was two times higher in large than in small HCC (48% vs 26%, p<0.008), and in more advanced tumor (stage 3 vs stages 1 and 2: 49% vs 21%, p<0.0007). HCC patients with mutated p53 gene had a worse outcome (5-year survival; 18% vs 38%, p<0.008). We conclude that p53 gene mutation is common in advanced HCC, occurs as a late event in HCC growth, correlates with tumor progression and aggression, and is a useful molecular prognostic parameter of HCC. The p53 mutation patterns did not correlate with HBV or HCV infection. The frequency of p53 mutations did not differ between Taiwanese patients and mainland Chinese in Taiwan. However, mutation at codon 249 was more common in Taiwanese patients (p<0.05), while mutations of other types more frequent in the mainlanders (p<0.03). Hence endogenous and exogenous factors other than aflatoxin may also play a role in p53 mutation in HCC.