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Molecular Genetics of Hepatocellular Carcinoma

  • Christopher J. Bakkenist
  • James O’D. McGee

Summary

The major exogenous agents underlying hepatocellular carcinoma have been identified and characterized in detail. These agents, which include hepatitis viruses and cirrhosis, function primarily as mitogens causing hepatocellular hyperplasia. Disorderly hepatocyte hyperplasia with concurrent mutagenesis may give rise to hepatocellular carcinoma. Little progress has been made in identifying either the somatic or germline mutations underlying the development of hepatocellular carcinoma. As such, the molecular genetics of hepatocellular carcinoma are not well understood. Hepatocyte mutagens include endogenous oxygen free radicals and H2O2, which may diffuse out of mitochondria and peroxisomes. Hepatocytes are also the location of cytochrome p450s, which catalase more than 60 different types of reaction concerned with the metabolism of steroids and fatty acids involved in hormone regulation and the metabolism of exogenous dietary-derived compounds. Hepatocyte microsomes are therefore the site of metabolic activation of many procarcinogens. Taken together, these reactions place the hepatocyte genome in a highly mutagenic environment. Hyperplasia greatly increases the rate at which mutations accumulate because the time for DNA repair is reduced, DNA replication has an intrinsic error, and cell division can result in rearrangements of the genome. However, no single tumor suppressor gene has been found to be preferentially inactivated or oncogene to be preferentially activated in hepatocellular carcinoma. The identified germline mutations predisposing to hepatocellular hyperplasia generally either increase hyperplasia (e.g., MHC) or the amount of endogenous mutagens produced in the hepatocyte (e.g., p450). Taken together, these data suggest that rather than being a genetic disease, hepatocellular carcinoma is a disease of a “chronically afflicted genome.”

Keywords

Hepatocellular Carcinoma Allelic Imbalance Porphyria Cutanea Tarda Transgenic Mouse Strain Virus Transgenic Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Parkin DM, Stjernsward J, Muir CS (1984) Estimates of the worldwide frequency of twelve major cancers. Bull World Health Organ 62:163–182PubMedGoogle Scholar
  2. 2.
    Okuda K, Ohnishi K (1987) Prognosis of hepatocellular carcinoma. In: Okuda K, Ishak KG (eds) Neoplasms of the liver. Springer, Tokyo, pp 407–416Google Scholar
  3. 3.
    Colombo M (1992) Hepatocellular carcinoma. J Hepatol 15:225–236PubMedGoogle Scholar
  4. 4.
    Okuda K (1992) Hepatocellular carcinoma: recent progress. Hepatology 15:948–963PubMedGoogle Scholar
  5. 5.
    Yu MC, Tong MJ, Govindarajan S, Henderson BE (1991) Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst 83:1820–1826PubMedGoogle Scholar
  6. 6.
    Yeh FS, Yu MC, Mo CC, Luo S, Tong MJ, Henderson BE (1989) Hepatitis B virus, aflatoxins, and hepatocellular carcinoma in southern Guangsi, China. Cancer Res 49:2506–2509PubMedGoogle Scholar
  7. 7.
    Munoz N, Bosch FX (1989) Epidemiology of hepatocellular carcinoma. In: Okuda K, Ishak KG (eds) Neoplasms of the liver. Springer, Tokyo, pp 3–21Google Scholar
  8. 8.
    Bosch FX, Munoz N (1991) Hepatocellular carcinoma in the world: epidemiological questions. In: Tabor E, Di Bisceglie AM, Rurcell RH (eds) Etiology, pathology and treatment of hepatocellular carcinoma in northern America. Gulf, Houston, pp 35–56Google Scholar
  9. 9.
    Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inove A, Yamazaki M, Kawashima T (1993) Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328:1797–1801PubMedGoogle Scholar
  10. 10.
    Chisari FV (1995) Hepatitis B virus transgenic mice: insights into the virus and disease. Hepatology 22:1316–1325PubMedGoogle Scholar
  11. 11.
    Beasley RP (1987) The major etiology of hepatocellular carcinoma. In: Fortner JC, Rhoads JE (eds) Accomplishment in cancer research. Lippincott, Philadelphia, pp 80–106Google Scholar
  12. 12.
    Beasley RP, Lin CC, Hwang LY, Chen CS (1981) Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22707 men in Taiwan. Lancet 2:1129–1133PubMedGoogle Scholar
  13. 13.
    Sakamoto M, Hirohashi S, Tsuda H, Ino Y, Shimosato Y, Yamasaki S, Makuuchi M, Hasegawa H, Terada M, Hosada Y (1988) Increasing incidence of hepatocellular carcinoma possibly associated with non-A, non-B hepatitis in Japan, disclosed by hepatitis B virus DNA analysis of surgically resected cases. Cancer Res 48:7294–7297PubMedGoogle Scholar
  14. 14.
    Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362PubMedGoogle Scholar
  15. 15.
    Kuo G, Choo QL, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Tegtmeier GE, Bonino F, Colombo M, Lee WS, Kuo C, Berger K, Shuster JR, Overby R, Bradley DW, Houghton M (1989) An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362–364PubMedGoogle Scholar
  16. 16.
    Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, Furuta S, Akahane Y, Nishioka K, Purcell RH (1990) Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 12:671–675PubMedGoogle Scholar
  17. 17.
    Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Tapias JM, Ventura M, Vall M, Bruguera M, Bru C, Castillo R, Rhodes J (1989) Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 2:1004–1006PubMedGoogle Scholar
  18. 18.
    Colombo M, Kuo G, Choo QL, Donato MF, Ninno ED, Tommasini M, Dioguardi N, Houghton M (1989) Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 2:1006–1008PubMedGoogle Scholar
  19. 19.
    Hasan F, Jeffers LJ, De Medina M, Reddy KR, Parker T, Schiff ER, Houghton M, Chao Q, Kuo G (1991) Hepatitis C-associated hepatocellular carcinoma. Hepatology 12:589–591Google Scholar
  20. 20.
    Kew MC, Houghton M, Choo QL, Kuo G (1990) Hepatitis C virus antibodies in southern African blacks with hepatocellular carcinoma. Lancet 335:873–874PubMedGoogle Scholar
  21. 21.
    Chen DS, Kuo GC, Sung JL, Lai MY, Sheu JC, Chen PJ, Yang PM, Hsu HM, Chang MH (1990) Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease: the Taiwan experience. J Infect Dis 162:817–822PubMedGoogle Scholar
  22. 22.
    Srivatanakul P, Parkin DM, Khlat M, Chenvidhya D, Chotiwan P, Insiripong S, L’Abbe KA, Wild CP (1991) Liver cancer in Thailand. II. A casecontrol study of hepatocellular carcinoma. Int J Cancer 48:329–332PubMedGoogle Scholar
  23. 23.
    Dazza MC, Meneses LV, Girard PM, Astagneau P, Villaroel C, Delaporte E, Larouze B (1993) Absence of a relationship between antibodies to hepatitis C virus and hepatocellular carcinoma in Mozambique. Am J Trop Med Hyg 48:237–242PubMedGoogle Scholar
  24. 24.
    Thomas HC (1996) Clinical features of viral hepatitis. In: Weatherall DJ, Ledingham JGG, Warrell DA (eds) Oxford textbook of medicine, 3rd edn. Oxford University Press, Oxford, pp 2061–2069Google Scholar
  25. 25.
    Gentilini P, Melani L, Riccardi D, Raggi V, Romanelli R (1994) Hepatocellular carcinoma and viral cirrhosis. Hepatology 20:764–765PubMedGoogle Scholar
  26. 26.
    Kew MC, Popper H (1984) Relationship between hepatocellular carcinoma and cirrhosis. Semin Liver Dis 4:136–146PubMedGoogle Scholar
  27. 27.
    Okuda K, Nakashima T, Kojiro M, Kondo Y, Wada K (1989) Hepatocellular carcinoma without cirrhosis in Japanese patients. Gasterenterology 97:140–146Google Scholar
  28. 28.
    Okuda K, Fujimoto I, Hanai A, Urano Y (1987) Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 47:4967–4972PubMedGoogle Scholar
  29. 29.
    Sheu JC, Sung JL, Chen DS, Lai MY, Wang TH, Yu JY, Yang PM, Chuang CN, Yang PC, Lee CS, Hsu HC, Mow SW (1985) Early detection of hepatocellular carcinoma by real-time ultrasonography: a prospective study. Cancer 56:660–666PubMedGoogle Scholar
  30. 30.
    Adami HO, Hsing AW, McLaughlin JK, Trichopoulos D, Hacker D, Ekbom A, Persson I (1992) Alcoholism and liver cirrhosis in the etiology of primary liver cancer. Int J Cancer 51:898–902PubMedGoogle Scholar
  31. 31.
    Tanaka A, Nei J, Takase S, Matsuda Y (1986) Effects of ethanol on experimental hepatocarcinogenesis. Hepatology 6:65–72Google Scholar
  32. 32.
    Sorenson TIA, Orholm M, Bentsen K, Hoybye C, Eghoe K, Christopherson P (1984) A prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet 2:241–244Google Scholar
  33. 33.
    Kew MC, Desmyter J, DeGroote G, Frosner G, Roggendorf M, Dienhardt F (1981) Hepatocellular cancer in southern African Blacks: HBeAg, anti-HBe, IgM-anti-HBc and other markers of hepatitis B. Prog Med Virol 27:41–48PubMedGoogle Scholar
  34. 34.
    Hirayama T (1989) A large-scale cohort study on risk factors for primary liver cancer, with special reference to the role of cigarette smoking. Cancer Chemother Pharmacol 23:S114–117PubMedGoogle Scholar
  35. 35.
    Kew MC (1989) Hepatocellular carcinoma with and without cirrhosis: a comparison in southern African Blacks. Gasterenterology 97:136–139Google Scholar
  36. 36.
    Linsell CA, Peers FG (1977) Aflatoxin and liver cell cancer. Trans R Soc Trop Med Hyg 71:471–473PubMedGoogle Scholar
  37. 37.
    Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. TIG 9:138–141PubMedGoogle Scholar
  38. 38.
    Weinberg RA (1989) Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res 49:3713–3721PubMedGoogle Scholar
  39. 39.
    Ames BN, Gold LS (1990) Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci USA 87:7772–7776PubMedGoogle Scholar
  40. 40.
    Wilson VL, Smith RA, Ma S, Cutler RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262:9948–9951PubMedGoogle Scholar
  41. 41.
    Steer CJ (1996) Liver regeration. FASEB J 9:1396–1400Google Scholar
  42. 42.
    Michalopoulos GK (1990) Liver regeneration: molecular mechanisms of growth control. FASEB J 4:176–187PubMedGoogle Scholar
  43. 43.
    Fausto N, Webber EM (1994) Liver regeneration. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter DA, Shafritz DA (eds) The liver; biology and pathobiology. Raven, New York, pp 1059–1084Google Scholar
  44. 44.
    Haber BA, Mohn KL, Diamond RH, Taub R (1993) Induction patterns of 70 genes during nine days after hepatectomy define the temporal course of liver regeneration. J Clin Invest 91:1319–1326PubMedGoogle Scholar
  45. 45.
    Thompson NL, Mead JE, Braun L, Goyette M, Shank PR, Fausto N (1986) Sequential protooncogene expression during rat liver regeneration. Cancer Res 46:3111–3117PubMedGoogle Scholar
  46. 46.
    Diehl AM, Yang SQ, Wolfgang D, Wand G (1992) Differential expression of guanine nucleotidebinding proteins enhances cAMP synthesis in regenerating rat liver. J Clin Invest 89:1706–1712PubMedGoogle Scholar
  47. 47.
    Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Wonde GF, Haronson SA (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251:802–804PubMedGoogle Scholar
  48. 48.
    Lok AS, Lai CC (1988) Factors determining the development of hepatocellular carcinoma in hepatitis B surface antigen carriers: a comparison between families with clusters and solitary cases. Cancer 61:1287–1291PubMedGoogle Scholar
  49. 49.
    Munoz N, Lingao A, Lao J, Esteve J, Viterbo G, Domingo EO, Lansang MA (1989) Patterns of familial transmission of HBV and the risk of developing liver cancer: a case-control study in the Philippines. Int J Cancer 44:981–984PubMedGoogle Scholar
  50. 50.
    Brechot C, Pourcel C, Louis A, Rain B, Tiollais P (1980) Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 286:533–535PubMedGoogle Scholar
  51. 51.
    Moroy T, Marchio A, Etiemble J, Trepo C, Tiollais P, Buendia MA (1986) Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature 324:276–279PubMedGoogle Scholar
  52. 52.
    Rogler CE (1990) Recent advances in hepatitis B viruses and hepatocellular carcinoma. Cancer Cells 2:366–369PubMedGoogle Scholar
  53. 53.
    De Souza A, Hankins GR, Washington MK, Fine RL, Orton TC, Jirtle RL (1995) Frequent loss of heterozygosity on 6q at the mannose-6-phosphate/ insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene 10:1725–1729PubMedGoogle Scholar
  54. 54.
    Farber E (1990) Clonal adaptation during carcinogenesis. Biochem Pharmacol 39:1837–1846PubMedGoogle Scholar
  55. 55.
    Dejean A, Bougueleret L, Grzesdrik KM, Tiollais P (1986) Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322:70–72PubMedGoogle Scholar
  56. 56.
    Simon D, Searles DB, Cao Y, Sun K, Knowles BB (1985) Chromosomal site of hepatitis B virus (HBV) integration in a human hepatocellular carcinoma-derived cell line. Cytogenet Cell Genet 29:116–120Google Scholar
  57. 57.
    Rogler CE, Sherman M, Su CY, Shafritz DA, Summers J, Shows TB, Henderson A, Kew M (1985) Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma. Science 230:319–322PubMedGoogle Scholar
  58. 58.
    DeLoia JA, Burk RD, Gearhart (1989) Developmental regulation of hepatitis B surface antigen expression in two lines of hepatitis B virus transgenic mice. J Virol 63:4069–4073PubMedGoogle Scholar
  59. 59.
    Farza H, Salmon AM, Hadchouel M, Moreau JL, Babinet C, Tiollais P, Pourcel C (1987) Hepatitis B surface antigen gene expression is regulated by sex steroids and glucocorticoids in transgenic mice. Proc Natl Acad Sci USA 84:1187–1191PubMedGoogle Scholar
  60. 60.
    Chisari FV, Filippi P, McLachlan A, Milich DR, Riggs M, Lee S, Palmiter RD, Pinkert CA, Brinster RL (1986) Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol 60:880–887PubMedGoogle Scholar
  61. 61.
    Moriyama T, Guilhot S, Klopchin K, Moss B, Pinkert CA, Palmiter RD, Brinster RL, Kanagawa O, Chisari FV (1990) Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science 248:361–364PubMedGoogle Scholar
  62. 62.
    Ando K, Moriyama T, Guidotti LG, Wirth S, Schreiber RD, Schlicht HJ, Huang S, Chisari FV (1993) Mechanisms of class I restricted immunopathology: a transgenic mouse model of fulminant hepatitis. J Exp Med 178:1541–1554PubMedGoogle Scholar
  63. 63.
    Ando K, Guidotti LG, Cerny A, Ishikawa T, Chisari FV (1994) CTL access to tissue antigen is restricted in vivo. J Immunol 153:482–488PubMedGoogle Scholar
  64. 64.
    Barnaba V, Franco A, Alberti A, Balsano C, Benvenuto R, Balsano F (1989) Recognition of hepatitis B virus envelope proteins by liverinfiltrating T lymphocytes in chronic HBV infection. J Immunol 143:2650–2655PubMedGoogle Scholar
  65. 65.
    Gilles PN, Guerrette DL, Ulevitch RJ, Schreiber RD, Chisari FV (1992) HBsAg retention sensitizes the hepatocyte to injury by physiological concentrations of interferon-gamma. Hepatology 16:655–663PubMedGoogle Scholar
  66. 66.
    Chisari FV, Filippi P, Buras J, McLachlan A, Popper H, Pinkert CA, Palmiter RD, Brinster RL (1987) Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci USA 84:6909–6913PubMedGoogle Scholar
  67. 67.
    Chisari FV, Klopchin K, Moriyma T, Pasquinelli C, Dunsford HA, Sell S, Pinkert CA, Brinster RL, Palmiter RD (1989) Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59:1145–1156PubMedGoogle Scholar
  68. 68.
    Dunsford HA, Sell S, Chisari FV (1990) Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res 50:3400–3407PubMedGoogle Scholar
  69. 69.
    Sell S, Hunt JM, Dunsford HA, Chisari FV (1991) Synergy between hepatitis B virus expression and chemical hepatocarcinogens in transgenic mice. Cancer Res 51:1278–1285PubMedGoogle Scholar
  70. 70.
    Huang SN, Chisari FV (1995) Strong, sustained hepatocellular proliferation precedes hepato-carcinogenesis in hepatitis B surface antigen transgenic mice. Hepatology 21:620–626PubMedGoogle Scholar
  71. 71.
    Hagen TM, Huang SN, Curnutte J, Fowler P, Martinez V, Wehr C, Ames BN, Chisari FV (1994) Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc Natl Acad Sci USA 91:12808–12812PubMedGoogle Scholar
  72. 72.
    Kim C-M, Koike K, Saito I, Miyamura T, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320PubMedGoogle Scholar
  73. 73.
    Koike K, Moriya K, Iino S, Yotsuyanagi H, Endo Y, Miyamura T, Hurokawa K (1994) High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology 19:810–819PubMedGoogle Scholar
  74. 74.
    Ueda H, Ullrich SJ, Gangemi JD, Kappel CA, Ngo L, Feitelson MA, Jay G (1995) Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet 9:41–47PubMedGoogle Scholar
  75. 75.
    Feitelson MA, Zhu M, Duan LX, London WT (1993) Hepatitis Bx antigen and p53 are asssociated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene 8:1109–1117PubMedGoogle Scholar
  76. 76.
    Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC (1994) Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 91:2230–2234PubMedGoogle Scholar
  77. 77.
    Unsal H, Yakicier C, Marcais DC, Kew M, Volkmann M, Zentgraf H, Isselbacher KJ, Ozturk M (1994) Genetic heterogeneity of hepatocellular carcinoma. Proc Natl Acad Sci USA 91:822–826PubMedGoogle Scholar
  78. 78.
    Seto E, Mitchel PS, Yen TSB (1990) Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 344:72–74PubMedGoogle Scholar
  79. 79.
    Maguire HF, Hoeffer JP, Siddiqui A (1991). HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 252:842–844PubMedGoogle Scholar
  80. 80.
    Schirmacher P, Held WA, Chisari FV, Yang D, Rogler CE (1992) Reactivation of insulin-like growth factor II during hepatocarcinogenesis in transgenic mice suggests a role in malignant growth. Cancer Res 52:2549–2556PubMedGoogle Scholar
  81. 81.
    Kuo MT, Jou JY, Teeter LD, Ikeguchi M, Chisari FV (1992) Activation of multidrug resistance (Pglycoprotein) mdr3/mdr1a gene during the development of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell Growth Differ 52:273–278Google Scholar
  82. 82.
    Pasquinelli C, Bhavani K, Chisari FV (1992) Multiple oncogenes and tumor suppressor genes are structurally and functionally intact during hepatocarcinogenesis in hepatitis B virus transgenic mice. Cancer Res 52:2823–2829PubMedGoogle Scholar
  83. 83.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedGoogle Scholar
  84. 84.
    Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350:427–428PubMedGoogle Scholar
  85. 85.
    Coursaget P, Depril N, Chabaud M, Nandi R, Mayelo V, LeCann P, Yvonnet B (1993) High prevalence of mutations at codon 249 of the p53 gene in hepatocellular carcinomas from Senegal. Br J Cancer 67:1395–1397PubMedGoogle Scholar
  86. 86.
    Bressac B, Kew M, Wands J, Ozturk M (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429–431PubMedGoogle Scholar
  87. 87.
    Aguilar F, Hussain SP, Cerutti P (1994) Aflatoxin B1 induces the transversion of G→T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci USA 90:8586–8590Google Scholar
  88. 88.
    Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P (1994) Geographic variation of p53 mutational profile in nonmalignant human liver. Science 264:1317–1319PubMedGoogle Scholar
  89. 89.
    Dumenco L, Oguey D, Wu J, Messler N, Fausto N (1995) Introduction of a murine p53 mutation corresponding to human codon 249 into a murine hepatocyte cell line results in growth advantage, but not in transformation. Hepatology 22:1279–1288PubMedGoogle Scholar
  90. 90.
    Fujimoto M, Hampton LL, Wirth PJ, Wang NJ, Xie JP, Thorgeirson SS (1994) Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China. Cancer Res 54:281–285PubMedGoogle Scholar
  91. 91.
    Miller RH, Purcell RH (1990) Hepatitis C virus shares amino acid sequence similarity with pestiviruses and flaviviruses as well as members of two plant virus supergroups. Proc Natl Acad Sci USA 87:2057–2061PubMedGoogle Scholar
  92. 92.
    Sakamuro D, Furukawa T, Takegami T (1995) Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J Virol 69:3893–3896PubMedGoogle Scholar
  93. 93.
    Simonetti RG, Camma C, Fiorello F, Cottone M, Rapicetta M, Marino L, Fioreni G, Craxi A, Ciccaglione A, Giusepetti R, Stroffolini T, Pagliaro L (1992) Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis: a case-control study. Ann Intern Med 116:97–102PubMedGoogle Scholar
  94. 94.
    Diamantis ID, McGandy CE, Chen T, Liaw Y, Gudat F, Bianchi L (1994) Detection of hepatitis B and C viruses in liver tissue with hepatocellular carcinoma. J Hepatol 20:405–409PubMedGoogle Scholar
  95. 95.
    El-Refaie A, Savage K, Bhattacharya S, Khakoo S, Harrison TJ, El-Batanony M, Soliman E-S, Nasr S, Mokhtar N, Amer K, Scheuer PJ, Dhillon AP (1996) HCV-associated hepatocellular carcinoma without cirrhosis. Hepatology 24:277–285Google Scholar
  96. 96.
    Negro F, Pacchioni D, Shimizu Y, Miller RH, Bussolati G, Purcell RH, Bonino F (1992) Detection of intrahepatic replication of hepatitis C virus RNA by in situ hybridization and comparison with histopathology. Proc Natl Acad Sci USA 89:2247–2251PubMedGoogle Scholar
  97. 97.
    Blight K, Rowland R, Hall P, Lesniewski RR, Trowbridge R, LaBrooy JT, Gowans EJ (1993) Immunohistochemical detection of the NS4 antigen of hepatitis C virus and its relation to histopathology. Am J Pathol 143:1568–1573PubMedGoogle Scholar
  98. 98.
    Liaw YF, Lee CS, Tsai SL, Liaw BO, Chen TC, Sheen IS, Chu CM (1995) T-cell-mediated autologous hepatocytotoxicity in patients with chronic hepatitis C virus infection. Hepatology 22:1368–1373PubMedGoogle Scholar
  99. 99.
    Minutello MA, Pileri P, Unutmaz D, Censini S, Kuo G, Houghton M, Brunetto MR, Bonine F, Abrignani S (1993) Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C. J Exp Med 178:17–25PubMedGoogle Scholar
  100. 100.
    Challen C, Lunec J, Warren W, Collier J, Bassendine MF (1992) Analysis of the p53 tumorsuppressor gene in hepatocellular carcinomas from Britain. Hepatology 16:1362–1364PubMedGoogle Scholar
  101. 101.
    Tanaka S, Toh Y, Adachi E, Matsumata T, Mori R, Sugimachi K (1993) Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation. Cancer Res 53:2884–2887PubMedGoogle Scholar
  102. 102.
    Nose H, Imazaeki F, Ohto M, Omata M (1993) p53 gene mutations and 17p allelic deletions in hepatocellular carcinoma from Japan. Cancer 72:355–360PubMedGoogle Scholar
  103. 103.
    Oda T, Tsuda H, Scarpa A, Sakamoto M, Hiroshi S (1992) p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res 52:6358–6364PubMedGoogle Scholar
  104. 104.
    Debuire B, Paterlini P, Pontisso P, Basso G, May E (1993) Analysis of the p53 gene in European hepatocellular carcinomas and hepatoblastomas. Oncogene 8:2303–2306PubMedGoogle Scholar
  105. 105.
    Volkmann M, Hofmann WJ, Muler M, Rath U, Otto G, Zentgraf H, Galle PR (1994) p53 overexpression is frequent in European hepatocellular carcinoma and largely independent of the codon 249 hot spot mutation. Oncogene 9:195–204PubMedGoogle Scholar
  106. 106.
    Ng I0, Chung LP, Tsang SW, Lam CL, Lai CS, Fan ST, Ng M (1994) p53 gene mutation spectrum in hepatocellular carcinomas in Hong Kong Chinese. Oncogene 9:985–990PubMedGoogle Scholar
  107. 107.
    Sheu JC, Huang GT, Lee PH, Chung JC, Chou HC, Lai MY, Wang JT, Lee HS, Shih LN, Yang PM, Wang TH, Chen DS (1992) Mutation of p53 gene in hepatocellular carcinoma in Taiwan. Cancer Res 52:6098–6100PubMedGoogle Scholar
  108. 108.
    Scorsone KA, Zhou YZ, Butel JS, Slagle BL (1992) p53 mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res 52:1635–1638PubMedGoogle Scholar
  109. 109.
    Kubicka S, Truatwein C, Schrem H, Tillman H, Manns M (1995) Low incidence of p53 mutations in European hepatocellular carcinomas with heterogeneous mutation as a rare event. J Hepatol 23:412–419PubMedGoogle Scholar
  110. 110.
    Fox TR, Watanabe PG (1985) Detection of a cellular oncogene in spontaneous liver tumors of B6C3F1 mice. Science 228:596–597PubMedGoogle Scholar
  111. 111.
    Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M (1987) Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327:298–303PubMedGoogle Scholar
  112. 112.
    Tada M, Omata M, Ohto M (1990) Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res 50:1121–1124PubMedGoogle Scholar
  113. 113.
    Nishida N, Fukuda Y, Komeda T, Kita R, Sando T, Furukawa M, Amenomori M, Shibagaki I, Nakao K, Ikenaga M, Ishizuki K (1994) Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res 54:3107–3110PubMedGoogle Scholar
  114. 114.
    Simon D, Knowles BB, Weith A (1991) Abnormalities of chromosome 1 and loss of heterozygosity on 1p in primary hepatomas. Oncogene 6:765–770PubMedGoogle Scholar
  115. 115.
    Kuroki T, Fujiwara Y, Tsuchiya E, Nakamori S, Imaoka S, Kanematsu T, Nakumura Y (1995) Accumulation of genetic changes during development and progression of hepatocellular carcinoma: loss of heterozygosity of chromosome arm 1p occurs at an early stage of hepatocarcinogenesis. Genes Chromosom Cancer 13: 163–167PubMedGoogle Scholar
  116. 116.
    Buetow KH, Murray JC, Israel JL, London WT, Smith M, Blanquet V, Brechot C, Redeker A, Govindarajah S (1989) Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc Natl Acad Sci USA 86:8852–8856PubMedGoogle Scholar
  117. 117.
    Fujimori M, Tokino T, Hino O, Kitagawa T, Imamura T, Okamoto E, Mitsunobu M, Ishikawa T, Nakagama H, Harada H, Yagura M, Matsubara K, Nakamura Y (1991) Allelotype study of primary hepatocellular carcinoma. Cancer Res 51:89–93PubMedGoogle Scholar
  118. 118.
    Konishi M, Kikuchi-Yanoshita R, Tanaka K, Sato C, Tsuruta K, Maeda Y, Koike M, Tanaka S, Nakamura Y, Hattori N, Miyaki M (1993) Genetic changes and histopathological grades in human hepatocellular carcinomas. Jpn J Cancer Res 84:893–899PubMedGoogle Scholar
  119. 119.
    Ding SF, Habib NA, Dooley J, Wood C, Bowles L, Delhanty JDA (1991) Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. Br J Cancer 64:1083–1087PubMedGoogle Scholar
  120. 120.
    Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagasse H, Ando H, Yanagisawa A, Tsuchiya E, Kato Y, Nakamura Y (1992) The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer. Cancer Res 52:6696–6698PubMedGoogle Scholar
  121. 121.
    Kuroki T, Fujiwara Y, Nakamori S, Imaoka S, Kanematsu T, Nakumura Y (1995) Evidence for the presence of two tumour-suppressor genes for hepatocellular carcinoma on chromosome 13q. Br J Cancer 72:383–385PubMedGoogle Scholar
  122. 122.
    Emi M, Fujiwara Y, Nakajima T, Tsuchiya E, Tsuda H, Hirohashi S, Maeda Y, Tsuruta K, Miyaki M, Nakamura Y (1992) Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer, and lung cancer. Cancer Res 52:5368–5372PubMedGoogle Scholar
  123. 123.
    Fujimori M, Monden M, Mori T, Nakamura Y, Emi M (1993) Frequent multiplication of the long arm of chromosome 8 in hepatocellular carcinoma. Cancer Res 53:857–860Google Scholar
  124. 124.
    Wang HP, Rogler CE (1988) Deletions in human chromosome arms 1 l and 13q in primary hepatocellular carcinomas. Cytogenet Cell Genet 48:72–78PubMedGoogle Scholar
  125. 125.
    Haber DA, Housman DE (1992) Role of the WT1 gene in Wilms’ tumour. Cancer Sury 12:105–117Google Scholar
  126. 126.
    Zhang X, Xu MJ, Murakami Y, Sachse R, Yasima K, Hirohashi S, Hu SX, Benedict WF, Sekiya T (1994) Deletions of chromosome 13q, mutations in retinoblastoma 1, and retinoblastoma protein state in human hepatocellular carcinoma. Cancer Res 54:4177–4182PubMedGoogle Scholar
  127. 127.
    Sato T, Tanigami A, Yamakawa K, Akiyama F, Kasui F, Sakamoto G, Nakamura Y (1990) Allelotype of breast cancer; cumulative allele losses promote tumour progression in primary breast cancer. Cancer Res 50:7184–7189PubMedGoogle Scholar
  128. 128.
    Tsuda H, Zhang W, Shimosato Y, Yokota J, Terada M, Sugimura T, Miyamura T, Hirohashi S (1990) Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma. Proc Natl Acad Sci USA 87:6791–6794PubMedGoogle Scholar
  129. 129.
    Stickland JE, Tomlinson IPM, Ramshaw AL, Bromley L, Potter CG, McGee JO’D (1993) Quantification of oncogene dosage in tumours by simultaneous dual-label hybridization. Oncogene 8:223–227PubMedGoogle Scholar
  130. 130.
    Tomlinson IPM, Gammack AJ, Stickland JE, Mann GJ, MacKie RM, Kefford RF, McGee JO’D (1993) Loss of heterozygosity in malignant melanoma at loci on chromosome 11 and 17 implicated in the pathogenesis of other cancers. Genes Chromosom Cancer 7:169–172PubMedGoogle Scholar
  131. 131.
    Bethwaite PB, Koreth J, Herrington CS, McGee JO’D (1995) Loss of heterozygosity occurs at the D11S29 locus on chromosome 11q23 in invasive cervical carcinoma. Br J Cancer 71:814–818PubMedGoogle Scholar
  132. 132.
    Koreth J, Bethwaite PB, McGee JO’D (1995) Mutation at chromosome 11q23 in human nonfamilial breast cancer: a microdissection microsatellite analysis. J Pathol 176:11–18PubMedGoogle Scholar
  133. 133.
    Jirtle RJ, Hankins GR, Reisenbichler H, Boyer IJ (1994) Regulation of mannose 6-phosphate/ insulin-like growth factor-II receptors and transforming growth factor beta during liver tumor promotion with phenobarbital. Carcinogenesis 15:1473–1478PubMedGoogle Scholar
  134. 134.
    Kornfield S (1992) Structure and function of the mannose-6-phosphate/insulin like growth factor II receptors. Annu Rev Biochem 61:307–330Google Scholar
  135. 135.
    Lee SJ, Nathans D (1988) Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors. J Biol Chem 263:3521–3527PubMedGoogle Scholar
  136. 136.
    Dennis PA, Rifkin DB (1991) Cellular activation of latent transforming growth factor beta requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor. Proc Natl Acad Sci USA 88:580–584PubMedGoogle Scholar
  137. 137.
    De Souza A, Hankins GR, Washington MK, Orton TC, Jirtle RL (1995) M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet 11:447–449PubMedGoogle Scholar
  138. 138.
    Xu Y, Goodyer CG, Deal C, Polychronakos C (1993) Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochem Biophys Res Commun 197:747–754PubMedGoogle Scholar
  139. 139.
    Ito H, Tashiro K, Stroud MR, Orntoft TF, Meldgaard P, Singhal AK, Hakomori SI (1991) Specificity and immunobiological properties of monoclonal antibody IMH2, established after immunization with Le(b)/Le(a) glycosphingolipid, a novel extended type 1 chain antigen. Cancer Res 51:4080PubMedGoogle Scholar
  140. 140.
    Yoo Y, Ueda H, Park K, Flanders KC, Lee YI, Jay G, Kim SJ (1996) Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator: role in HBV pathogenesis. J Clin Invest 97:388–395PubMedGoogle Scholar
  141. 141.
    Carbonara A, Mayr W, Rizzetto M, Contu L, Curtoni ES, DeMarchi M, Farci P, Lavarini C, Olivetti E (1983) Endemic HBV infection, tissue autoantibodies and HLA: analysis of a Sardinian population. Tissue Antigens 22:289–293PubMedGoogle Scholar
  142. 142.
    Board PG, Coggan M, Johnston P, Ross V, Suzuki T, Webb G (1990) Genetic heterogeneity of the human glutathione transferases: a complex of gene families. Pharmacol Ther 48:357–369PubMedGoogle Scholar
  143. 143.
    Brockmoller J, Kerb R, Drakoulis N, Nitz M, Roots I (1993) Genotype and phenotype of glutathione S-transferase class mu isoenzymes mu and psi in lung cancer patients and controls. Cancer Res 53:1004–1011PubMedGoogle Scholar
  144. 144.
    Skoda RC, Demierre A, McBride OW, Gopnzalez FJ, Meyer UA (1988) Human microsomal xenobiotic epoxide hydrolase: complementary DNA sequence, complementary DNA-directed expression in COS-1 cells, and chromosomal localization. J Biol Chem 263:1549–1554PubMedGoogle Scholar
  145. 145.
    Hasset C, Aicher L, Sidhu S, Omiecinski CJ (1994) Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet 3:421–428Google Scholar
  146. 146.
    McGlynn KA, Rosvold EA, Lustbader ED, Hu Y, Clapper ML, Zhou T, Wild CP, Xia XL, Baffoe Bonnie A, Ofori-Adjei D, Chen GC, London WT, Shen FM, Buetow KH (1995) Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci USA 92:2384–2386PubMedGoogle Scholar
  147. 147.
    Weinberg AG, Mize CE, Worthen HG (1976) The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Pediatr 88:434–438PubMedGoogle Scholar
  148. 148.
    MacSween RNM, Scott AR (1973) Hepatic cirrhosis: a clinico-pathological review of 520 cases. J Clin Pathol 26:936–942PubMedGoogle Scholar
  149. 149.
    Salata H, Cortes JM, Enriquez de Salamanca RE, Oliva H, Castro A, Kusak E, Carreno V, Hernandez-Guio C (1985) Porphyria cutanea tarda and hepatocellular carcinoma: frequency of occurrence and related factors. J Hepatol 1:477–487PubMedGoogle Scholar
  150. 150.
    Drinkwater NR (1994) Genetic control of hepatocarcinogenesis in C3H mice. Drug Metab Rev 26:201–208PubMedGoogle Scholar
  151. 151.
    Gariboldi M, Manenti G, Canzian F, Falvella FS, Pierotti MA, Porta GD, Binelli G, Dragani TA (1993) Chromosome mapping of murine susceptibility loci to liver carcinogenesis. Cancer Res 53:209–211PubMedGoogle Scholar
  152. 152.
    Poole TM, Drinkwater NR (1996) Two genes abrogate the inhibition of murine hepatocarcinogenesis by ovarian hormones. Proc Natl Acad Sci USA 93:5848–5853PubMedGoogle Scholar
  153. 153.
    Vesselinovitch SD, Mihailovich (1967) The effect of gonadectomy on the development of hepatomas induced by urethane. Cancer Res 27:1788–179PubMedGoogle Scholar
  154. 154.
    Yamamoto R, Iishi H, Tatsuta M, Tsuji M, Terada N (1991) Roles of ovaries and testes in hepatocellular tumorigenesis induced in mice by 3′-methyl-4-dimethylaminoazobenzene. Int J Cancer 49:83–88PubMedGoogle Scholar
  155. 155.
    Poole TM, Drinkwater NR (1995) Hormonal and genetic interactions in murine hepatocarcinogenesis. Proc Clin Biol Res 391:187–194Google Scholar
  156. 156.
    Poole TM, Drinkwater NR (1996) Strain dependent effects of sex hormones on hepatocarcinogenesis in mice. Carcinogenesis 17:191–196PubMedGoogle Scholar
  157. 157.
    Parkin DM, Pisani P, Ferlay J (1993) Estimates of the worldwide mortality from eighteen major cancers in 1985: implications for prevention and projections of future burden. Int J Cancer 54:594–606PubMedGoogle Scholar
  158. 158.
    Gold LS, Slone TH, Manley NB, Bernstein L (1991) Target organs in chronic bioassays of 533 chemical carcinogens. Environ Health Perspect 93:233–246PubMedGoogle Scholar

Copyright information

© Springer Japan 1997

Authors and Affiliations

  • Christopher J. Bakkenist
    • 1
  • James O’D. McGee
    • 1
  1. 1.Nuffield Department of Pathology and Bacteriology, John Radcliffe HospitalOxford UniversityHeadington, OxfordUK

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