Mutations in the HFE gene and their interaction with exogenous risk factors in hepatocellular carcinoma

The possible role of iron in facilitating the development of liver cancer i s still debated, The aims of this study were to define the prevalence of th e mutations 845G -->A, and 187C -->G (C282Y and H63D) in the HFE gene assoc iated with hereditary hemochromatosis in Italian patients with hepatocellul ar carcinoma occurring in cirrhosis and to analyze the interaction between these mutations and other established risk factors for hepatocellular carci noma. The HFE gene mutations, performed by polymerase chain reaction, were analyzed in 81 patients (63 males, 18 females) with hepatocellular carcinom a. None of the patients had a phenotype compatible with homozygous heredita ry hemochromatosis. Interaction between I HFE mutations and exogenous risk factors was analyzed by collecting information on alcohol consumption, hepa titis B and C virus infections, and iron status at the time of diagnosis of chronic liver disease. This analysis was performed only in males to rule o ut gender influence on patients' iron status by using the case-only approac h specifically designed to estimate departure from multiplicative risk rati os under the assumption of independence between genotype and environmental exposure. The prevalence of the C282Y mutation was significantly higher in patients with hepatocellular carcinoma than in normal controls (8.6% vs 1.6 %, P <0.03). At univariate analysis, iron overload was significantly associ ated with both HFE mutations (P <0.0001), whereas ongoing hepatitis B virus infection was associated with the C282Y mutation (P <0.05). By multivariat e analysis, a trend for an increased risk of being positive for hepatitis v irus markers (OR2.9, CI 95%0.9-9.5) and of having been alcohol abusers (OR3 , CI 95%0.7-14) was observed in patients heterozygous for the HFE mutations , These data indicate that the prevalence of the main mutation associated w ith hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus in fections or who had been alcohol abusers could have an increased risk of de veloping cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors, (C) 2001 Academic Press.