Mutations of the HFE gene and the risk of hepatocellular carcinoma

The discovery of the C282Y and H63D point mutations in the hereditary hemoc hromatosis-associated HFE gene allows us to study the molecular basis of co ngenital and acquired iron overload disorders. In hereditary hemochromatosi s an increased frequency of the C282Y and, to a lesser extent, of the H63D mutations has been established, but their role in other conditions associat ed with iron overload and their prevalence in the normal population are sti ll under investigation. We sought to determine the presence of such mutatio ns, and their possible involvement in the multi-step neoplastic transformat ion of the hepatocytes, in patients diagnosed with hepatocellular carcinoma , a frequent complication of iron-induced liver cirrhosis occurring in untr eated hereditary hemochromatosis subjects. The frequency of the C282Y and H 63D mutations was determined in DNA from 12 patients with hepatocellular ca rcinoma and with no clinical signs of hereditary hemochromatosis. The frequ ency of the mutations was also determined in 130 normal subjects. A germlin e C282Y mutation was found in none of the hepatocellular carcinoma patients ; the frequency of the H63D mutation was not increased, compared to the 130 controls. The allele frequencies of the C282Y and H63D mutations in the no rmal population were 0.042 and 0.185, respectively. In conclusion, we sugge st that the hereditary hemochromatosis-related mutations of the HFE gene do not play a significant role in the pathogenesis of hepatocellular carcinom a.