Expression and Hypomethylation of α-Fetoprotein Gene in Unicentric and Multicentric Human Hepatocellular Carcinomas



The messenger RNA and DNA methylation of the α-fetoprotein gene were studied in 101 resected primary hepatocellular carcinomas, of which 93 were unicentric and 8 were multicentric. Fifty-five were 5 cm or less in diameter (small) and 46 were more than 5 cm in diameter (large). In 48.5% of the cases, we detected α-fetoprotein messenger RNA in hepatocellular carcinomas, more frequently in large (60.9%) than in small (38.2%; p < 0.00001) but not in any of the nontumorous livers. The α-fetoprotein messenger RNA was detected in 83%, 70% and 6.8% of patients with serum α-fetoprotein levels of 320 ng/ml or more, 100 to 319 ng/ml and less than 100 ng/ml, respectively. This finding suggests that α-fetoprotein gene expression in hepatocellular carcinoma contributes to the serum α-fetoprotein elevation in patients with hepatocellular carcinoma. α-Fetoprotein messenger RNA appeared as a major band of 2.4 kb, with two minor species of about 6.5 and 3.6 kb in the hepatocellular carcinoma and the fetal liver. Hypomethylation of the 5′ end of the α-fetoprotein gene was detected in 78.3% of hepatocellular carcinomas expressing α-fetoprotein messenger RNA but infrequently (16.7%) in hepatocellular carcinomas with no detectable α-fetoprotein messenger RNA (p < 0.0003). This finding suggests that hypomethylation at the 5′ region of the gene is associated with α-fetoprotein gene reexpression in hepatocellular carcinoma. The α-fetoprotein gene expression helped to differentiate unicentric from multicentric hepatocellular carcinomas and to identify other hidden α-fetoprotein-secreting hepatocellular carcinomas. The α-fetoprotein gene expression occurred more often in patients younger than 30 yr old (100% vs. 41.2%; p < 0.002), in HBsAg-seropositive patients (53.2% vs. 33.3%; p < 0.03) and in patients with poorly differentiated hepatocellular carcinoma (56% vs. 23.1%; p < 0.003). Patients with unicentric small hepatocellular carcinomas expressing α-fetoprotein messenger RNA or serum α-fetoprotein elevation had a worse 2-yr survival rate than those with neither α-fetoprotein messenger RNA expression nor serum α-fetoprotein elevation (70.6% vs. 94.7%; p < 0.02). We conclude that the α-fetoprotein gene expression in hepatocellular carcinoma possesses biological significance. (HEPATOLOGY 1993;17:35–41.)