title: Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study.
abstract: BACKGROUND
  Although most patients with hereditary haemochromatosis have HFE C282Y mutations, the lifetime risk to HFE C282Y homozygotes of developing fatal diseases such as hepatocellular carcinoma is uncertain. We have carried out a cross-sectional study to determine the proportion of diagnosed hepatocellular carcinoma patients who are homozygous for the HFE C282Y mutation; and to estimate the penetrance of this genotype with respect to hepatocellular carcinoma in East Anglia.
  
  
  METHODS
  Tissue biopsies were analysed from 144 cases of hepatocellular carcinoma for HFE C282Y mutations; the data produced were compared with the frequency of HFE mutations in a large sample of the local population. Data were also retrieved from the East Anglian Cancer Intelligence Unit to determine the annual incidence of hepatocellular carcinoma; and from appropriate life tables.
  
  
  RESULTS
  Eight out of 144 of the cases were homozygous for the HFE C282Y mutation, all 8 cases were male. 6 of these 8 cases had a previous diagnosis of hereditary haemochromatosis. Male HFE C282Y homozygotes were more likely to be diagnosed with hepatocellular carcinoma (odds ratio [OR] = 14, 95% confidence interval [CI] = 5-37). For this population, we estimate that the penetrance of the HFE C282Y homozygous genotype, with respect to hepatocellular carcinoma, was between 1.31 % and 2.1% for males and was zero for females.
  
  
  CONCLUSIONS
  In this population, we found that only a very small proportion of homozygotes for the HFE C282Y mutation developed hepatocellular carcinoma. However, individuals with this genotype have a significantly increased risk of this rare disease relative to those who do not carry the mutations.
authors.affiliation: Department of Molecular Genetics, Norfolk and Norwich University Hospital, Norwich, NR47UY, UK. gavin.willis@nnuh.nhs.uk
authors.forename: Gavin
authors.initials: G
authors.lastname: Willis
authors.forename: Vicky
authors.initials: V
authors.lastname: Bardsley
authors.forename: Ian W
authors.initials: IW
authors.lastname: Fellows
authors.forename: Ray
authors.initials: R
authors.lastname: Lonsdale
authors.forename: Jennie Z
authors.initials: JZ
authors.lastname: Wimperis
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Jennings
mesh_terms: D000375:Aging; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003545:Cysteine; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D019683:Penetrance; D014443:Tyrosine
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014443:Tyrosine; D003545:Cysteine