Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study

详细信息    查看全文

• 作者：Gavin Willis (1)
  Vicky Bardsley (2)
  Ian W Fellows (3)
  Ray Lonsdale (2)
  Jennie Z Wimperis (4)
  Barbara A Jennings (5)
  
• 刊名：BMC Gastroenterology
• 出版年：2005
• 出版时间：December 2005
• 年：2005
• 卷：5
• 期：1
• 全文大小：516KB
• 参考文献：1. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G: Long term survival in patients with hereditary haemochromatosis. / Gastroenterology 1996, 110:1107-119. CrossRef
  2. Fracanzani AL, Conte D, Fraquelli M, Taioli E, Mattioli M, Losco A, Fargion S: Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. / Hepatology 2001, 33:647-51. CrossRef
  3. Elmberg M, Hultcrantz R, Ekbom A, Brandt L, Olsson S, Olsson R, Lindgren S, Loof L, Stal P, Wallerstedt S, Almer S, Sandberg-Gertzen H, Askling J: Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. / Gastroenterolology 2003, 125:1733-741. CrossRef
  4. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G: Survival and causes of death in cirrhotic and in non cirrhotic patients with primary haemochromatosis. / N Engl J Med 1985, 313:1256-2. CrossRef
  5. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK: A novel MHC class I-like gene is mutated in patients with hereditary hemochromatosis. / Nature Genet 1996, 13:399-08. CrossRef
  6. Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R, Pockros P, Kosty M, Venditti CP, Phatak PD, Seese NK, Chorney KA, Ten Elshof AE, Gerhard GS, Chorney M: Mutation analysis in hereditary hemochromatosis. / Blood Cells Mol Dis 1996, 22:187-94. CrossRef
  7. The UK Haemochromatosis Consortium: A simple genetic test identifies 90% of UK patients with haemochromatosis. / Gut 1997, 41:841-4. CrossRef
  8. Bassett ML, Leggett BA, Halliday JW, Webb S, Powell LW: Analysis of the cost of population screening for haemochromatosis using biochemical and genetic markers. / Hepatology 1997, 27:517-24. CrossRef
  9. Burt MJ, George PM, Upton JD, Collett JA, Frampton CM, Chapman TM, Walmsley TA, Chapman BA: The significance of haemochromatosis gene mutations in the general population: implications for screening. / Gut 1998, 43:830-36. CrossRef
  10. Willis G, Wimperis JZ, Lonsdale R, Fellows IW, Watson MA, Skipper LM, Jennings BA: Incidence of liver disease in people with HFE mutations. / Gut 2000, 46:401-04. CrossRef
  11. Willis G, Wimperis JZ, Lonsdale R, Jennings BA: Haemochromatosis gene mutation in hepatocellular cancer. / Lancet 1997, 350:365-66. CrossRef
  12. Willis G, Scott DGI, Jennings BA, Smith K, Bukhari M, Wimperis JZ: HFE mutations in an inflammatory arthritis population. / Rheumatology 2002, 41:176-79. CrossRef
  13. Sampson MJ, Williams T, Heyburn PJ, Greenwood RH, Temple RC, Wimperis JZ, Jennings BA, Willis GA: HFE Prevalence of HFE Haemochromatosis gene mutations in unselected male patients with Type 2 diabetes. / J Lab Clin Med 2000, 135:170-73. CrossRef
  14. Halsall DJ, McFarlane I, Luan J, Cox TM, Wareham NJ: Typical type 2 diabetes mellitus and HFE gene mutations: a population-based case-control study. / Hum Mol Genet 2003, 12:1361-365. CrossRef
  15. Government Actuary's Department Life tables [http://www.gad.gov.uk/Life_Tables/Interim_life_tables.htm]
  16. East Anglian Cancer Intelligence Unit [http://www.phpc.cam.ac.uk/ciu/]
  17. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RNM, Phillips MJ, Portmann BG, Poulsen H, Scheuer PJ, Schmid M, Thaler H: Histological grading and staging of chronic hepatitis. / J Hepatol 1995, 22:696-99. CrossRef
  18. Willis G, Wimperis JZ, Smith KC, Fellows IW, Jennings BA: HFE (haemochromatosis gene) C282Y homozygotes in an elderly male population. / Lancet 1999, 354:221-22. CrossRef
  19. Willis G, Wimperis JZ, Smith K, Fellows IW, Jennings BA: HFE mutations in the elderly. / Blood Cells Mol Dis 2003, 31:240-46. CrossRef
  20. Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, Napier JA, Worwood M: HFE mutations, iron deficiency and overload in 10500 blood donors. / Br J Haematol 2001, 114:474-4. CrossRef
  21. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T: Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. / Lancet 2002, 359:211-18. CrossRef
  22. Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG: Hemochromatosis mutations in the general population: iron overload progression rate. / Blood 2004, 103:2914-919. CrossRef
  23. Willis G, Jennings BA, Goodman E, Fellows IW, Wimperis JZ: A high prevalence of HLA-H 845A mutations in hemochromatosis patients and the normal population in eastern England. / Blood Cells Mol Dis 23:288-91.
  24. Blanc JF, De Ledinghen V, Bernard PH, de Verneuil H, Winnock M, Le Bail B, Carles J, Saric J, Balabaud C, Bioulac-Sage P: Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular carcinoma developed in non-cirrhotic liver. / J Hepatol 2000, 32:805-11. CrossRef
  25. Cauza E, Peck-Radosavljevic M, Ulrich-Pur H, Datz C, Gschwantler M, Schoniger-Hekele M, Schoniger-Hekele M, Hackl F, Polli C, Rasoul-Rockenschaub S, Muller C, Wrba F, Gangl A, Ferenci P: Mutations of the HFE gene in patients with hepatocellular carcinoma. / Am J Gastroenterol 2003, 98:442-47. CrossRef
  26. Bray F, Sankila R, Ferlay J, Parkin DM: Estimates of cancer incidence and mortality in Europe in 1995. / Eur J Cancer 2002, 38:99-66. CrossRef
  27. Kazemi-Shirazi L, Datz C, Maier-Dobersberger T, Kaserer K, Hackl F, Polli CT, Steindl PE, Penner E, Ferenci P: The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C. / Gastroenterology 1999, 116:127-34. CrossRef
  28. Datz C, Haas T, Rinner H, Sandhofer F, Patsch W, Paulweber B: Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferring saturation, and haemoglobin in young women: a protective role against iron deficiency? / Clin Chem 1998, 44:2429-432.
  29. Racchi O, Mangerini R, Rapezzi D, Gaetani GF, Nobile MT, Picciotto A, Ferraris AM: Mutations of the HFE gene and the risk of hepatocellular carcinoma. / Blood Cells Mol Dis 1999, 25:350-53. CrossRef
  30. Pirisi M, Toniutto P, Uzzau A, Fabris C, Avellini C, Scott C, Apollonio L, Beltrami CA, Bresadola F: Carriage of HFE mutations and outcome of surgical resection for hepatocellular carcinoma in cirrhotic patients. / Cancer 2000, 89:297-02. CrossRef
  31. Lauret E, Rodriguez M, Gonzalez S, Linares A, Lopez-Vazquez A, Martinez-Borra J, Rodrigo L, Lopez-Larrea C: HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma. / Am J Gastroenterol 2002, 97:1016-021. CrossRef
  32. Boige L, Castera L, de Roux N, Ganne-Carrie N, Ducot B, Pelletier G, Beaugrand M, Buffet C: Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis. / Gut 2003, 52:1178-181. CrossRef
  33. Fargion S, Fracanzani AL, Piperno A, Braga M, D'Alba R, Ronchi G, Fiorelli G: Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis. / Hepatology 1994, 20:1426-431. CrossRef
  34. Scotet V, Merour MC, Mercier AY, Chanu B, Le Faou T, Raguenes O, Le Gac G, Mura C, Nousbaum JB, Ferec C: Hereditary hemochromatosis: effect of excessive alcohol consumption on disease expression in patients homozygous for the C282Y mutation. / Am J Epidemiol 2003, 158:129-34. CrossRef
  35. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/5/17/prepub
  
• 作者单位：Gavin Willis (1)
  Vicky Bardsley (2)
  Ian W Fellows (3)
  Ray Lonsdale (2)
  Jennie Z Wimperis (4)
  Barbara A Jennings (5)
  
  1. Department of Molecular Genetics, Norfolk and Norwich University Hospital, Norwich, NR47UY, UK
  2. Department of Histopathology, Norfolk and Norwich University Hospital, Norwich, NR47UY, UK
  3. Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, NR47UY, UK
  4. Department of Haematology, Norfolk and Norwich University Hospital, Norwich, NR47UY, UK
  5. School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR47PT, UK
  

文摘

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] = 5-7). 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. Conclusion 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.