Gene–Environmental Interactions and Susceptibility to Liver Cancer

  • John B. ColerangleEmail author


Human liver cancer, specifically hepatocellular carcinoma (HCC), is the fifth most common malignancy worldwide and remains a major cause of cancer death. HCC accounts for over half a million deaths per year. Despite many efforts to understand the pathogenesis of HCC, little is known about its etiology. Hepatitis B and C, and aflatoxin B are the only established cause, and the proportion of cases of liver cancer attributed to Hepatitis B and C and aflatoxin B is about 75–80%. A family history of liver cancer accounts for only 3% of the cases of this disease. The remaining portions of cases are due to yet unrecognized factors. Alcohol is an important risk factor for the development of HCC since hepatic cirrhosis caused by chronic alcohol abuse has long been recognized as a major risk factor for the development of HCC. The pathogenesis of HCC is quite diverse and influenced by a variety of environmental and genetic factors of the host. The link between environmental factors, genetics, and the development of cancer has advanced our understanding of the factors that influence cancer risk. Understanding the relative roles of the environmental factors and genes in cancer etiology may clearly elucidate how each of these factors can disparately affect the health of individual members of a community. Although environmental, occupational, and recreational exposures to carcinogens contribute to cancer risk in humans, variation in incidence and progression of cancer in a population is due to genetic polymorphisms in the population. Functional polymorphisms that influence an individual’s susceptibility to liver cancer include gene products involved in activation and detoxification of carcinogens and DNA repair. Gene polymorphisms that play key roles in apoptosis may also provide insight to individual susceptibility to liver cancer. Thus genetic polymorphisms may explain why individuals with shared environmental exposures do not always share cancer morbidity and mortality.


Hepatocellular carcinoma (HCC) Hepatitis B and C Aflatoxin B Alcohol Functional polymorphisms in genes involved in activation and detoxification of carcinogens and DNA repair Influence an individual’s susceptibility to liver cancer 


  1. Adams, P. C. 1998. Hepatocellular carcinoma in hereditary hemochromatosis. Can. J. Gastroenterol. 129:946–995.Google Scholar
  2. Adams, P. C., Speechley, M., Kertesz, A. E. 1991. Long-term survival analysis in hereditary hemochromatosis. Gastroenterology 101:368–372.PubMedGoogle Scholar
  3. Akao, T. 2000. Competition in the metabolism of glycyrrhizin with glycyrrhetic acid mono-glucuronide by mixed Eubacterium sp. GLH and Ruminococcus sp. PO1-3. Biol. Pharm. Bull. 23:149–154.PubMedCrossRefGoogle Scholar
  4. Ambs, S., Bennett, W. P., Merriam, W. G., Ogunfusika, M. O., Oser, S. M., Harrington, A. M., Shields, P. G., Felley-Bosco, E., Hussain, S. P., Harris, C. C. 1999. Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. J. Natl. Cancer Inst. 91:86–88.PubMedCrossRefGoogle Scholar
  5. Ambs, S., Bennett, W. P., Merriam, W. G., Ogunfusika, M. O., Oser, S. M., Khan, A. et al. 1998a. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br. J. Cancer 78:233–239.PubMedCrossRefGoogle Scholar
  6. Ambs, S., Bennett, W. P., Merriam, W. G., Ogunfusika, M. O., Oser, S. M., Khan, M. A., Ambs, S., Hussain, S. P., Harris, C. C. 1997. Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression. FASEB J. 11:443–448.PubMedGoogle Scholar
  7. Ambs, S., Ogunfusika, M. O., Merriam, W. G., Bennett, W. P., Billiar, T. R., Harris, C. C. 1998b. Upregulation of NOS2 expression in cancer-prone p53 knockout mice. Proc. Natl. Acad. Sci. U.S.A. 95:8823–8828.PubMedCrossRefGoogle Scholar
  8. American Cancer Society (ACS). 2001. Cancer facts and figures. Liver cancer. American Cancer Society, Atlanta, GA.Google Scholar
  9. Araki, Y., Okamura, S., Hussain, S. P., Nagashima, M., He, P., Shiseki, M., Miura, K., Harris, C. C. 2003. Regulation of cyclooxygenase-2 expression by the wnt and ras pathways. Cancer Res. 63:728–734.PubMedGoogle Scholar
  10. Arata, Y., Fujita, M., Ohtani, K., Kijima, S., Kato, J. Y. 2000. Cdk2-dependent and -independent pathways in E2F-mediated S-phase induction. J. Biol. Chem. 275:6337–6345.Google Scholar
  11. Asare, G. A., Mossanda, K. S., Kew, M. C., Paterson, A. C., Kahler-Venter, C. P., Siziba, K. 2006a. Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity. Toxicology 219:41–52.PubMedCrossRefGoogle Scholar
  12. Asare, G. A., Paterson, A. C., Kew, M. C., Khan, S., Mossanda, K. S. 2006b. Iron-free neoplastic nodules and hepatocellular carcinoma without cirrhosis in Wistar rats fed a diet high in iron. J. Pathol. 208:82–90.PubMedCrossRefGoogle Scholar
  13. Ashburn, S. P., Han, X., Liehr, J. G. 1993. Microsomal hydroxylation of 2- and 4-fluoroestradiol to catechol metabolites and their conversion to methyl ethers: catechol estrogens as possible mediators of hormonal carcinogenesis. Mol. Pharmacol. 43:534–541.PubMedGoogle Scholar
  14. ASTDR. 1993. U. S. Public Health Service. Toxicological profile for vinyl chloride (update). Atlanta, GA. U. S. Public Health Service. (DHHS Publication No. TP–92/20).Google Scholar
  15. ASTDR. 1997. Toxicological profile of vinyl chloride. Update (Final Report). NTIS Accession No. P898101132. Atlanta, GA, pp. 274.Google Scholar
  16. Barbain, A., Bartsch, M. 1986. Mutagenic and promutagenic properties of DNA adducts formed by vinyl chloride metabolites. In The role of cyclic nucleic acid adducts in carcinogenesis and mutagenesis, vol. 70. Singer, B. and Bartsch, H. eds. International Agency for Research on Cancer, Lyons, pp. 345–358.Google Scholar
  17. Benhar, M., Engelberg, D., Levitzki, A. 2002. Reactive oxygen stress, stress activated kinases and stress signalling in cancer. EMBO Rep. 3:420–425.PubMedCrossRefGoogle Scholar
  18. Benn, J., Schneider, R. J. 1994. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc. Natl. Acad. Sci. U.S.A. 91:10350–10354.PubMedCrossRefGoogle Scholar
  19. Benn, J., Schneider, R. J. 1995. Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. Proc. Natl. Acad. Sci. U.S.A. 92(24):11215–11219.PubMedCrossRefGoogle Scholar
  20. Benowitz, S. 2007. Liver Cancer Biomarkers Struggling to Succeed. JNCI News 99(8):590–591.CrossRefGoogle Scholar
  21. Black, A. R., Azizkhan-Clifford, J. 1999. Regulation of E2F: A family of transcription factors involved in proliferation control. Gene 237:281–302.PubMedCrossRefGoogle Scholar
  22. Block, T. M., Mehta, A. S., Fimmel, C. J., Jordan, R. 2003. Molecular viral oncology of hepatocellular carcinoma. Oncogene 22:5093–5107.PubMedCrossRefGoogle Scholar
  23. Blumberg, R. S., Chopra, S., Ibrahim, R., Crawford, J., Farraye, Y., Zeldis, J., Berman, M. 1988. Primary hepatocellular carcinoma in idiopathic hemochromatosis: occurrence in non-cirrhotic patients. Gastroenterology 95:1399–1402.PubMedGoogle Scholar
  24. Bomford, A., Williams, R. 1967. Long-term results of venesection therapy in idiopathic hemochromatosis. Quart. J. Med. 45:611–623.Google Scholar
  25. Bothwell, T. H., Bradlow, B. A. 1960. Siderosis in the Bantu: a combined histopathological and chemical study. Arch. Path. 70:279–292.PubMedGoogle Scholar
  26. Brand, N., Petkovich, M., Krust, A., Chambon, P., de Thé, H., Marchio, A., Tiollais, P., Dejean, A. 1988. Identification of a second human retinoic acid receptor. Nature 332:850–853.PubMedCrossRefGoogle Scholar
  27. Bredt, D. S., Snyder, S. H. 1994. Nitric oxide: a physiologic messenger molecule. Annu. Rev. Biochem. 63:175–195.PubMedCrossRefGoogle Scholar
  28. Buchanan, F. G., DuBois, R. N. 2006. Connecting COX-2 and Wnt in cancer. Cancer Cell 9:6–8.PubMedCrossRefGoogle Scholar
  29. Buetow, K. H., Murray, J. C., Israel, J. L., London, W. T., Smith, M., Kew, M., Blanquet, V., Brechot, C., Redeker, A., Gonvindarajah, S. 1989. Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc. Natl. Acad. Sci. U.S.A. 86:8852–8856.PubMedCrossRefGoogle Scholar
  30. Bui, Q. D., Weisz, J. 1989. Monooxygenase mediating catecholestrogen formation by rat anterior pituitary is an estrogen-4-hydroxylase. Endocrinology 124:1085–1087.PubMedCrossRefGoogle Scholar
  31. Cadenzas, E. 1989. Biochemistry of oxygen toxicity. Annu. Rev. Biochem. 58:79–110.CrossRefGoogle Scholar
  32. Cai, L., Wang, G. J., Mukherjee, K., Xu, Z. L., Khalil, M., Cherian, M. G., Chakrabarti, S. 1999. Endothelins and their receptors in cirrhotic and neoplastic livers of Canadian and Chinese populations. Anticancer Res. 19:2243–2247.PubMedGoogle Scholar
  33. Campbell, J. S., Hughes, S. D., Gilbertson, D. G., Palmer, T. E., Holdren, M. S., Haran, A. C., Odell, M. M., Bauer, R. L., Ren, H. P., Haugen, H. S., Yeh, M. M., Fausto, N. 2005. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc. Natl. Acad. Sci. U.S.A. 102:3389–3394.PubMedCrossRefGoogle Scholar
  34. Caselmann, W. H. 1995. Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis. J. Hepatol. 22:34–37.PubMedCrossRefGoogle Scholar
  35. Castellone, M. D., Teramoto, H., Williams, B. O., Druey, K. M., Gutkind, J. S. 2005. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science. 310:1504–1510.PubMedCrossRefGoogle Scholar
  36. Cavalieri, E. L., Stack, D. E., Devanesan, P. D., Todorovic, R., Dwivedy, I., Higginbotham, S., Johansson, S. L., Patil, K. D., Gross, M. L., Gooden, J. K., Ramanathan, R., Cerny, R. L., Rogan, E. G. 1997. Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc. Natl. Acad. Sci. U.S.A. 94(20):10937–10942.PubMedCrossRefGoogle Scholar
  37. Cheeseman, K. H. 1993. Lipid peroxidation in cancer. In DNA and free radicals. Halliwell, B., and Arouma, A. I. Eds. Ellis Horwood, London, pp. 109–144.Google Scholar
  38. Chen, Z. M., Liu, B. Q., Boreham, J., Wu, Y. P., Chen, J. S., Peto, R. 2003. Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths. Int. J. Cancer 107(1):106–112.PubMedCrossRefGoogle Scholar
  39. Chen, H., Liu, J., Merrick, A., Waalkes, M. P. 2000. Genetic events associated with arsenite-induced malignant transformation: application of cDNA microarray technology. Mol. Carcinog. 30:75–87.Google Scholar
  40. Chen, H., Liu, J., Merrick, B. A., Waalkes, M. P. 2001. Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology. Mol. Carcinogen. 30:80–87.CrossRefGoogle Scholar
  41. Cheng, K. C., Cahill, D. S., Kasai, H., Nishimura, S., Loeb, L. A. 1992. 8-Hydroxyl guanine, an abundant form of oxidative DNA damage, causes G-T and A-C substitutions. J. Biol. Chem. 267:166–172.PubMedGoogle Scholar
  42. Chiba, T., Matsuzaki, Y., Abei, M., Shoda, J., Tanaka, N., Osuga, T., Aikawa, T. 1996. The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am. J. Gastroenterol. 91:1195–1203.PubMedGoogle Scholar
  43. Chou, M. W., Chen, W. 1997. Food Restriction Reduces Aflatoxin B1 (AFB1)-DNA Adduct Formation, AFB1-Glutathione Conjugation, and DNA Damage in AFB1-Treated Male F344 Rats and B6C3F1 Mice. The Journal of Nutrition. 127(2):210–217.PubMedGoogle Scholar
  44. Cottingham, K. 2009. Candidate biomarkers for liver cancer. J. Proteom. Res. 8(2):428.CrossRefGoogle Scholar
  45. Dabbagh, A. J., Mannion, T., Lynch, S. M., Frei, B. 1994. The effect of iron overload on rat plasma and liver oxidant status in vivo. Biochem. J. 300:799–803.PubMedGoogle Scholar
  46. DeVivo, I., Marion, M. J., Smith, S. J., Carney, W. P., Brandt-Rauf, P. W. 1994. Mutant c-Ki-ras p21 protein in chemical carcinogenes is in humans exposed to vinyl chloride. Cancer Causes Control 5:273–278.CrossRefGoogle Scholar
  47. Deugnier, Y., Turlin, B. 1998. Iron and neoplasia. J. Hepatol. 28:21–25.PubMedCrossRefGoogle Scholar
  48. Devereux, T. R., Stern, M. C., Flake, G. P., Yu, M. C., Zhang, Z. Q., London, S. J., Taylor, J. A. 2001. CTNNB1 mutations and betacatenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. Mol. Carcinog. 31:68–73.PubMedCrossRefGoogle Scholar
  49. Du, Q., Park, K. S., Guo, Z., He, P., Nagashima, M., Shao, L., Sahai, R., Geller, D. A., Hussain, S. P. 2006. Regulation of human nitric oxide synthase 2 expression by Wnt beta-catenin signaling. Cancer Res. 66:7024–7031.PubMedCrossRefGoogle Scholar
  50. Du, C. L., Wang, J. D. 1998. Increased morbidity odds ratio of primary liver cancer and cirrhosis of the liver among vinyl chloride monomer workers. Occup. Environ. Med. 55:528–532.PubMedCrossRefGoogle Scholar
  51. Dwivedy, I., Devanesan, P., Cremonesi, P., Rogan, E., Cavalieri, E. S. 1992. ynthesis and characterization of estrogen 2,3- and 3,4-quinones. Comparison of DNA adducts formed by the quinones versus horseradish peroxidase-activated catechol estrogens. Chem. Res. Toxicol. 5:828–833.PubMedCrossRefGoogle Scholar
  52. Eaton, D. L., Gallagher, E. P. 1994. Mechanisms of aflatoxin carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 34:135–172.PubMedCrossRefGoogle Scholar
  53. El-Serag, H. B. 2001. Epidemiology of hepatocellular carcinoma. Clin. Liver Dis. 5(1):87–107.PubMedCrossRefGoogle Scholar
  54. El-Serag, H. B., Mason, A. C. 2000. Risk factors for the rising rates of primary liver cancer in the United States. Arch. Intern. Med. 160:3227–3230.PubMedCrossRefGoogle Scholar
  55. Elmore, L., Hancock, A., Chang, S. F., Wang, X., Chang, S., Callahan, C., Geller, D., Will, H., Harris, C. C. 1997. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc. Natl. Acad. Sci. U.S.A. 94:14707–14712.PubMedCrossRefGoogle Scholar
  56. Esterbauer, H. 1993. Cytotoxicity and genotoxicity of lipid-oxidation products. Am. J. Clin. Nutr. 57(Suppl.):779–860.Google Scholar
  57. Esterbauer, H., Schaur, R. J., Zollner, H. 1991. Chemistry and biochemistry of 4-hydroxynonenal, malondialdehyde and related aldehydes. Free Radic. Biol. Med. 11(1):81–128.PubMedCrossRefGoogle Scholar
  58. Farazi, P. A., DePinho, R. A. 2006. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer 6:674–687; Source of Figures 4 and 5.PubMedCrossRefGoogle Scholar
  59. Fernandez, E., La Vecchia, C., D’Avanzo, B., Negri, E., Franceschi, S. 1994. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 3(3):209–212.PubMedGoogle Scholar
  60. Forrester, K., Ambs, S., Lupold, S. E., Kapust, R. B., Spillare, E. A., Weinberg, W. C., Felley-Bosco, E., Wang, X. W., Geller, D. A., Tzeng, E., Billiar, T. R., Harris, C. C. 1996. Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase (NOS2) expression by wild-type p53. Proc. Natl. Acad. Sci. U.S.A. 93:2442–2447.PubMedCrossRefGoogle Scholar
  61. Foy, E., Li, K., Sumpter, R., Loo, Y. M., Johnson, C. L., Wang, C., Fish, P. M., Yoneyama, M., Fujita, T., Lemon, S. M., Gale, M. 2005. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc. Natl. Acad. Sci. U.S.A. 102:2986–2991.PubMedCrossRefGoogle Scholar
  62. Francanzani, A. L., Conte, D., Fraquelli, M., Taioli, E., Mattioli, M., Losco, A., Fargioni, S. 2001. 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 33:647–665.CrossRefGoogle Scholar
  63. Fujimori, M., Tokino, T., Hino, O., Kitagawa, T., Imamura, T., Okamoto, E., Mitsunobu, M., Ishikawa, T., Nakagawa, H., Harada, H., Yagura, M., Matsubara, K., Nakamura, Y. 1991. Allelotype study of primary hepatocellular carcinoma. Cancer Res. 51:89–93.PubMedGoogle Scholar
  64. Fujimoto, H., Sasaki, J., Matsumoto, M., Suga, M., Ando, Y., Iggo, R., Tada, M., Saya, H., Ando, M. 1998. Significant correlation of nitric oxide synthase activity and p53 gene mutation in stage I lung adenocarcinoma. Jpn. J. Cancer Res. 89:696–702.PubMedCrossRefGoogle Scholar
  65. Garr, B. I., Flickinger, J. C., Lotze, M. T. 1997. Cancer of the liver. In Principles and practice of oncology, 5th Edition. Devita, T., Hellman, S., and Rosenberg, S. eds. Lippincott-Raven Publishers, Philadelphia, PA, pp. 1271–1297.Google Scholar
  66. Giannitrapani, L., Soresi, M., La Spada, E., Cervello, M., D’alessandro, N., Montalto, G. 2006. Sex hormones and risk of liver tumor. Ann. N. Y. Acad. Sci. 1089(1):228–236.PubMedCrossRefGoogle Scholar
  67. Goering, P. L., Aposhian, H. V., Mass, M. J., Cebrian, M., Beck, B. D., Waalkes, M. P. 1999. The enigma of arsenic carcinogenesis: role of metabolism. Toxicol. Sci. 49:5–14.PubMedCrossRefGoogle Scholar
  68. Gonzalez-Amaro, R., Garcia-Monzon, C., Garcia-Buey, L., Moreno-Otero, R., Alonso, J. L., Yague, E., Pivel, J. P., Lopez-Cabrera, M., Fernandez-Ruiz, E., Sanchez-Madrid, F. 1994. Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis. J. Exp. Med. 179:841–848.PubMedCrossRefGoogle Scholar
  69. Gordeuk, V. R., Boyd, R. D., Brittenham, G. H. 1986. Dietary iron overload persists in sub-Saharan Africa. Lancet 1:1310–1313.PubMedCrossRefGoogle Scholar
  70. Gordeuk, V. R., McLaren, C. E., MacPhail, A. P., Deichsel, D., Bothwell, T. H. 1996. Associations of iron overload in Africa and hepatocellular carcinoma and tuberculosis. Blood 87:3476–3479.Google Scholar
  71. Greenblatt, M. S., Bennett, W. P., Hollstein, M., Harris, C. C. 1994. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54:4855–4878.PubMedGoogle Scholar
  72. Gupta, R. A., DuBois, R. N. 2001. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat. Rev. Cancer 1:11–21.PubMedCrossRefGoogle Scholar
  73. HSDB. 2003. Hazardous Substances Database. Vinyl chloride. National Library of Medicine. Last updated: 8/29/03.Google Scholar
  74. Hagen, T. M., Huang, S., Curnutte, J., Fowler, P., Martinez, V., Wehr, C. M., Ames, B. N., Chisari, F. V. 1994. Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc. Natl. Acad. Sci. U.S.A. 91:12808–12812.PubMedCrossRefGoogle Scholar
  75. Han, X., Liehr, J. G. 1994. 8-Hydroxylation of guanine bases in kidney and liver DNA of hamsters treated with estradiol: role of free radicals in estrogen-induced carcinogenesis. Cancer Res. 54:5155–5157.Google Scholar
  76. Han, X., Liehr, J. G. 1994. DNA single strand breaks in kidneys of Syrian hamsters treated with steroidal estrogens. Hormone-induced free radical damage preceding renal malignancy. Carcinogenesis 15:997–1000.PubMedCrossRefGoogle Scholar
  77. Han, X., Liehr, J. G. 1995. Microsome-mediated 8-hydroxylation of guanine bases of DNA by steroid estrogens: correlation of DNA damage by free radicals with metabolic activation to quinones. Carcinogenesis 16:2571–2574.PubMedCrossRefGoogle Scholar
  78. Hartwig, A. 1998. Carcinogenicity of metal compounds: possible role of DNA repair inhibition. Toxicol. Lett. 102–103:235–239.PubMedCrossRefGoogle Scholar
  79. Henderson, A. S., Ripley, S., Hino, O., Rogler, C. E. 1988. Identification of a chromosomal aberration associated with a hepatitis B DNA integration site in human cells. Cancer Genet. Cytogenet. 30:269–275.PubMedCrossRefGoogle Scholar
  80. Hino, O., Ohtake, K., Rogler, C. E. 1989. Features of two hepatitis B virus (HBV) DNA integrations suggest mechanisms of HBV integration. J. Virol. 63:2638–2643.PubMedGoogle Scholar
  81. Hino, O., Shows, T. B., Rogler, C. E. 1986. Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17:18 translocation. Proc. Natl. Acad. Sci. U.S.A. 83(21):8338–8342.PubMedCrossRefGoogle Scholar
  82. Hino, O., Tabatat, S., Hottat, Y. 1991. Evidence for increased in vitro recombination with insertion of human hepatitis B virus DNA. Proc. Natl. Acad. Sci. U.S.A. 88:9248–9252.PubMedCrossRefGoogle Scholar
  83. Hollstein, M., Marion, M. -J., Lehman, T., Welsh, J., Harris, C. C., Martel-Planche, G., Kuster, I., Montesano, R. 1994. p53 mutations at A: T base pairs in angiosarcomas of vinyl-chloride-exposed factory workers. Carcinogenesis 15:1–3.PubMedCrossRefGoogle Scholar
  84. Hsing, A. W., McLaughlin, J. K., Hrubec, Z., Blot, W. J., Fraumeni, J. F., Jr. 1990. Cigarette smoking and liver cancer among US veterans. Cancer Causes Control 1:217–221.PubMedCrossRefGoogle Scholar
  85. Hsing, A. W., McLaughlin, J. K., Olsen, S. H., Mellemkjar, L., Waholder, S., Fraumeni, J. F. 1995. Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark. Int. J. Cancer 60:60–162.CrossRefGoogle Scholar
  86. Huang, X. J., Wiernik, P. H., Klein, R. S., Gallagher, R. E. 1999. Arsenic trioxide induces apoptosis of myeloid leukemia cells by activation of caspases. Med. Oncol. 16:58–64.PubMedCrossRefGoogle Scholar
  87. Hussain, S. P., Hofseth, L. J., Harris, C. C. 2001. Tumor suppressor genes: at the crossroads of molecular carcinogenesis, molecular epidemiology and human risk assessment. Lung Cancer 34(2):S7–S15.PubMedCrossRefGoogle Scholar
  88. Hussain, S. P., Hofseth, L. J., Harris, C. C. 2003. Radical causes of cancer. Nat. Rev. Cancer 3:276–285.PubMedCrossRefGoogle Scholar
  89. Hussain, S. P., Raja, K., Amstad, P. A., Sawyer, M., Trudel, T. J., Wogan, G. N., Hofseth, L. J., Shields, P. G., Billiar, T. R., Trautwein, C., Hohler, T., Galle, P. R., Phillips, D. H., Markin, R., Marrogi, A. J., Harris, C. C. 2000. Increased p53 mutation load in non-tumorous human liver of Wilson disease and haemochromatosis: oxyradical overload disease. Proc. Natl. Acad. Sci. U.S.A. 97:12770–12775.PubMedCrossRefGoogle Scholar
  90. Hussain, S. P., Schwank, J., Staib, F., Wang, X. W., Harris, C. C. 2007. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26:2166–2176.PubMedCrossRefGoogle Scholar
  91. Hwang, H. J., Kim, G. J., Lee, G. B., Oh, J. T., Chun, Y. H., Park, S. H. 2003. A comprehensive karyotypic analysis on Korean hepatocellular carcinoma cell lines by cross-species color banding and comparative genomic hybridization. Cancer Genet. Cytogenet. 141:128–137.PubMedCrossRefGoogle Scholar
  92. Ichiba, M., Maeta, Y., Mukoyama, T., Saeki, T., Yasui, S., Kanbe, T., Okano, J. I., Tanabe, Y., Hirooka, Y., Yamada, S., Kurimasa, A., Murawaki, Y., Shiota, G. 2003. Expression of 8-hydroxy-20-deoxyguanosine in chronic liver disease and hepatocellular carcinoma. Liver Int. 23(5):338–345.PubMedCrossRefGoogle Scholar
  93. International Agency for Research on Cancer. 2002. Aflatoxins. IARC Monogr. Eval. Carcinog. Risks Hum. 82:171–300.Google Scholar
  94. International Agency for Research on Cancer. IARC. 1993. Some naturally occurring substances: food items and constituents. IARC Monogr. Eval. Carcinog. Risks Hum. 56:245–395.Google Scholar
  95. Johnson, D. G., Walker, C. L. 1999. Cyclins and cell cycle checkpoints. Annu. Rev. Pharmacol. Toxicol. 39:295–312.PubMedCrossRefGoogle Scholar
  96. Jungst, C., Cheng, B., Gehrke, R., Schmitz, V., Nischalke, H. D., Ramakers, J., Schramel, P., Schirmacher, P., Sauerbruch, T., Caselmann, W. H. 2004. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 39:1663–1672.PubMedCrossRefGoogle Scholar
  97. Kane, J. M., III, Shears, L. L., Hierholzer, C., Ambs, S., Billiar, T. R., Posner, M. C. 1997. Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis. J. Surg. Res. 69:321–324.PubMedCrossRefGoogle Scholar
  98. Kato, J. 1999. Induction of S-phase by G1 regulatory factors. Front Biosci. 4:787–792.CrossRefGoogle Scholar
  99. Kew, M. C., Popper, H. 1984. The relationship between hepatocellular carcinoma and cirrhosis. Semin. Liver Dis. 4:136–146.PubMedCrossRefGoogle Scholar
  100. Kielhorn, J., Melber, C., Wahnschaffe, U., Aitio, A., Mangelsdorf, I. 2000. Vinyl chloride: still a cause for concern. Environ. Health Perspect. 108(7):579–588.PubMedCrossRefGoogle Scholar
  101. Kim, Y. M., Chung, H. T., Simmons, R. L., Billiar, T. R. 2000. Cellular non-heme iron content is a determinant of nitric oxide-mediated apoptosis, necrosis, and caspase inhibition. J. Biol. Chem. 275:10954–10961.PubMedCrossRefGoogle Scholar
  102. Kim, S. F., Huri, D. A., Snyder, S. H. 2005. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science 310:1966–1970.PubMedCrossRefGoogle Scholar
  103. Kirk, G. D., Bah, E., Montesano, R. 2006. Molecular epidemiology of human liver cancer: insights into etiology, pathogenesis and prevention from The Gambia, West Africa. Carcinogenesis 27(10):2070–2082.PubMedCrossRefGoogle Scholar
  104. Kirk, G. D. ,, Lesi, O. A., Mendy, M., Akano, A. O., Sam, O., Goedert, J. J., Hainaut, P., Hall, A. J., Whittle, H., Montesano, R. 2004. The Gambia liver cancer study: infection with hepatitis B and C and the risk of hepatocellular carcinoma in West Africa. Hepatology 39(1):211–219.PubMedCrossRefGoogle Scholar
  105. Kirk, G. D., Turner, P. C., Gong, Y. et al. 2005. Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity. Cancer Epidemiol. Biomarkers Prev. 14:373–379.PubMedCrossRefGoogle Scholar
  106. Kirkman, H. 1959. Estrogen-induced tumors of the kidney in the Syrian hamster. III: growth characteristics in the Syrian hamster. Natl. Cancer Inst. Monogr. 1:1–57.PubMedGoogle Scholar
  107. Kitay-Cohen, Y., Amiel, A., Ashur, Y., Fejgin, M. D., Herishanu, Y., Afanasyev, F., Bomstein, Y., Lishner, M. 2001. Analysis of chromosomal aberrations in large hepatocellular carcinomas by comparative genomic hybridization. Cancer Genet. Cytogenet. 131:60–64.PubMedCrossRefGoogle Scholar
  108. Knudson, A. G. 1986. Genetics of human cancer. Annu. Rev. Genet. 20:231–251.PubMedCrossRefGoogle Scholar
  109. Kowdley, K. V. 2004. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127:S79–S86.PubMedCrossRefGoogle Scholar
  110. Kuchino, Y., Mori, F., Kasai, H., Inoue, H., Iwai, S., Miura, K. 1989. Misreading of DNA templates containing 8-hydroxydeoxguanosine at the modified base and at adjacent residues. Nature 327(6117):77–79.CrossRefGoogle Scholar
  111. Kusano, N., Okita, K., Shirahashi, H., Harada, T., Shiraishi, K., Oga, A., Kawauchi, S., Furuya, T., Sasaki, K. 2002. Chromosomal imbalances detected by comparative genomic hybridization are associated with outcome of patients with hepatocellular carcinoma. Cancer 94:746–751.PubMedCrossRefGoogle Scholar
  112. Lang, A. J., Mirski, S. E., Cummings, H. J., Yu, Q., Gerlach, J. H., Cole, S. P. 1998. Structural organization of the human TOP2A and TOP2B genes. Gene 221:255–266.PubMedCrossRefGoogle Scholar
  113. Lange-Carter, C. A., Pleiman, C. M., Gardner, A. M., Blumer, K. J., Johnson, G. L. 1993. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260:315–319.PubMedCrossRefGoogle Scholar
  114. Laskin, D. L., Heck, D. E., Laskin, J.MD. 1998. Role of inflammatory cytokines and nitric oxide in hepatic and pulmonary toxicity. Toxicol. Lett. 102–103:289–293.PubMedCrossRefGoogle Scholar
  115. Levine, A. J., Momand, J., Findlay, C. A. 1991. The p53 tumor suppressor gene. Nature 351:453–456.PubMedCrossRefGoogle Scholar
  116. Li, K., Foy, E., Ferreon, J., Nakamura, M., Ferreon, A. C., Ikeda, M., Ray, S. C., Gale, M., Lemon, S. M. 2005. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. U.S.A. 102:2992–2997.PubMedCrossRefGoogle Scholar
  117. Li, Y., Trush, M. A., Yager, J. D. 1994. DNA damage caused by reactive oxygen species orginating from a copper-dependent oxidation of the 2-hydroxycatechol of estradiol. Carcinogenesis 15:1421–1427.PubMedCrossRefGoogle Scholar
  118. Liehr, J. G., Ulubelen, A. A., Strobel, H. W. 1986. Cytochrome P-450-mediated redox cycling of estrogens. J. Biol. Chem. 261:16865–16870.PubMedGoogle Scholar
  119. Liu, F., Jan, K. Y. 2000. DNA damage in arsenite- and cadmium-treated bovine aortic endothelial cells. Free Radic. Biol. Med. 28:55–63.PubMedCrossRefGoogle Scholar
  120. Liu, D. N., Lu, X. Z., Li, B. L., Zhou, D. X., Li, F. X., Zheng, D. H., Wang, K. H. 1992. Clinical analysis of 535 cases of chronic arsenic poisoning from coal burning. Chin. J. Med. 31:560–562.Google Scholar
  121. Loeb, L. A., James, E. A., Waltersdorph, A. M., Klebanofrf, S. J. 1988. Mutagenesis by the autoxidation of iron with isolated DNA. Proc. Natl. Acad. Sci. U.S.A. 85:3918–3932.PubMedCrossRefGoogle Scholar
  122. Lombard, D. B., Guarente, L. 2000. Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres. Cancer Res. 60:2331–2334.PubMedGoogle Scholar
  123. London, W. T., McGlynn, K. A. 1996. Liver cancer. In Cancer epidemiology and prevention, 2nd Edition. Schottenfeld, D., Fraumeni, J. F. eds. Oxford University Press, New York, NY.Google Scholar
  124. Lu, T., Liu, J., LeCluyse, E. L., Zhou, Y. -S., Cheng, M. -L., Waalkes, M. P. 2001. Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol. Sci. 59:185–192.PubMedCrossRefGoogle Scholar
  125. Lucito, R., Schneider, R. J. 1992. Hepatitis B virus X protein activates transcription factor NF-kappa B without a requirement for protein kinase C. J. Virol. 66:983–991.PubMedGoogle Scholar
  126. Lunn, R. M., Langlois, R. G., Hsieh, L. L., Thompson, C. L., Bell, D. A. 1999. XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res. 59:2557–2561.PubMedGoogle Scholar
  127. Lynn, S., Shiung, J. N., Gurr, J. -R., Jan, K. Y. 1998. Arsenite stimulates poly(ADP-ribosylation) by generation of nitric oxide. Free Radic. Biol. Med. 24:442–449.PubMedCrossRefGoogle Scholar
  128. MacSween, R. N., Scott, A. R. 1973. Hepatic fibrosis: a clinico-pathological review of 520 cases. J. Clin. Pathol. 26:9369–9942.Google Scholar
  129. Maguire, H. F., Hoeffler, J. P., Siddiqui, A. 1991. HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 252:842–844.PubMedCrossRefGoogle Scholar
  130. Majumder, M., Ghosh, A. K., Steele, R., Ray, R., Ray, R. B. 2001. Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J. Virol. 75:1401–1407.PubMedCrossRefGoogle Scholar
  131. Mandishoma, E., MacPhail, A. P., Gordeuk, V. R., Kedda, M. A., Paterson, A. C., Rouault, T. A., Kew, M. C. et al. 1998. Dietary iron overload as a risk factor for hepatocellular carcinoma in Black Africans. Hepatology 27:1563–1566.CrossRefGoogle Scholar
  132. Marrogi, A. J., Khan, M. A., van Gijssel, H. E., Welsh, J. A., Rahim, H., Demetris, A. J., Kowdley, K. V., Hussain, S. P., Nair, J., Bartsch, H., Okby, N., Poirier, M. C., Ishak, K. G., Harris, C. C. 2001. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma. J. Natl. Cancer Inst. 93:1652–1655.PubMedCrossRefGoogle Scholar
  133. Martucci, C. P., Fishman, J. 1993. P450 enzymes of estrogen metabolism. Pharmacol. Ther. 57:237–257.PubMedCrossRefGoogle Scholar
  134. Mazumder, D. N., Das Gupta, J., Santra, A., Pal, A., Ghose, A., Sarkar, S. 1998. Chronic arsenic toxicity in West Bengal—the worst calamity in the world. J. Indian Med. Assoc. 96:4–7.PubMedGoogle Scholar
  135. McClain, C. J., Hill, D. B., Song, Z., Deaciuc, I., Barve, S. 2002. Monocyte activation in alcoholic liver disease. Alcohol 27:53–61.PubMedCrossRefGoogle Scholar
  136. Melen, K., Fagerlund, R., Nyqvist, M., Keskinen, P., Julkunen, I. 2004. Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J. Med. Virol. 73:536–547.PubMedCrossRefGoogle Scholar
  137. Meneghini, R. 1997. I ron homeostasis, oxidative stress, and DNA damage. Free Radic. Biol. Med. 23:783–792.PubMedCrossRefGoogle Scholar
  138. Mihm, S., Hutschenreiter, A., Fayyazi, A., Pingel, S., Ramadori, G. 1996. High inflammatory activity is associated with an increased amount of IFN-gamma transcripts in peripheral blood cells of patients with chronic hepatitis C virus infection. Med. Microbiol. Immunol. (Berlin) 185:95–102.CrossRefGoogle Scholar
  139. Moodie, S. A., Willumsen, M. B., Weber, M. J., Wolfman, A. 1993. Complexes of Ras-GTP with Raf-1 and Mitogen-Activated Protein Kinase Kinase. Science 260:1658–1661.PubMedCrossRefGoogle Scholar
  140. Morris, J. S., Schmid, M., Newman, S., Scheuer, P. J., Sherlock, S. 1974. Arsenic and noncirrhotic portal hypertension. Gastroenterology 66:86–94.PubMedGoogle Scholar
  141. Moyo, V. M., Makinuke, R., Gangaudzo, I. T., Gordeuk, V. R., McLaren, V. R. 1996. Associations of iron overload in Africa and hepatocellular carcinoma and tuberculosis. Blood 87:3470–3476.Google Scholar
  142. Muller, H., Helin, K. 2000. The E2F transcription factors: key regulators of cell proliferation. Biochim. Biophys. Acta 1470:M1–M12.PubMedGoogle Scholar
  143. Nagaya, T., Nakamura, T., Tokino, T., Tsurimoto, T., Imai, M., Mayumi, T., Kamino, K., Yamamura, K., Matsubara, K. 1987. The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma. Genes Dev. 1:773–782.PubMedCrossRefGoogle Scholar
  144. Nathan, C., Xie, Q. W. 1994. Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–918.PubMedCrossRefGoogle Scholar
  145. National Cancer Institute (NCI). 1978. Vinyl chloride: an information resource. DHEW (NIH) Publication No. 79–1599, Bethesda, MD.Google Scholar
  146. National Research Council (NRC). 1999. Arsenic in drinking water. National Academy Press, Washington, D.C.Google Scholar
  147. Natoli, G., Avantaggiati, M. L., Chirillo, P., Costanzo, A., Artini, M., Balsano, C., Levrero, M. 1994. Induction of the DNA-binding activity of c-jun/c-fos heterodimers by the hepatitis B virus transactivator pX. Mol. Cell Biol. 14:989–998.PubMedGoogle Scholar
  148. Naugler, W. E., Sakurai, T., Kim, S., Maeda, S., Kim, K. H., Elsharkawy, A. M., Karin, M. 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 317(5834):121–124.PubMedCrossRefGoogle Scholar
  149. Nevens, F., Fevery, J., Van Steenbergan, W., Sciot, R., Desmet, V., De Groot, J. 1990. Arsenic and non-cirrhotic portal hypertension. A report of eight cases. J. Hepatol 11:80–85.PubMedCrossRefGoogle Scholar
  150. Newbold, R. R., Bullock, B. C., McLachlan, J. A. 1990. Uterine adenocarcinoma in mice following developmental treatment with estrogen. Cancer Res. 50:7677–7681.PubMedGoogle Scholar
  151. Niederau, C., Fischer, R., Sonnenberg, A., Stremmel, W., Trampisch, H. J., Strohmeyer, G. 1985. Survival and causes of death in cirrhotic and noncirrhotic patients with primary hemochromatosis. N. Engl. J. Med. 313:1256–1262.PubMedCrossRefGoogle Scholar
  152. Okabe, H., Ikai, I., Matsuo, K., Satoh, S., Momoi, H., Kamikawa, T., Katsura, N., Nishitai, R., Takeyama, O., Fukumoto, M., Yamaoka, Y. 2000. Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and-negative tumors. Hepatology 31:1073–1079.PubMedCrossRefGoogle Scholar
  153. Omary, M. B., Ku, N. O. 1997. Intermediate filament proteins of the liver: emerging disease association and functions. Hepatology 25:1043–1048.PubMedCrossRefGoogle Scholar
  154. Pachiadakis, I., Pollara, G., Chain, B. M., Naoumov, N. V. 2005. Is hepatitis C virus infection of dendritic cells a mechanism facilitating viral persistence? Lancet Infect. Dis. 5:296–304.PubMedCrossRefGoogle Scholar
  155. Paria, B. C., Chakraborty, C., Dey, S. K. 1990. Catecholestrogen formation in mouse uterus and its role in implantion. Mol. Cell. Endocrinol 69:25–31.PubMedCrossRefGoogle Scholar
  156. Park, K. J., Choi, S. H., Choi, D. H., Park, J. M., Yie, S. W., Lee, S. Y., Hwang, S. B. 2003. Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2. J. Biol. Chem. 278:30711–30718.PubMedCrossRefGoogle Scholar
  157. Perera, F. P. 1996. Molecular epodemiology: insight into cancer susceptibility, risk assessment, and prevention. J. Natl. Cancer Inst. 88:496–509.PubMedCrossRefGoogle Scholar
  158. Perkin, D. M., Bray, F. I., Devasa, S. S. 2001. Cancer burden in the year 2000. The global picture. Eur. J. Cancer 37(8):54–66.Google Scholar
  159. Petrowsky, H., Schmandra, T., Lorey, T., Hanisch, E., Herrmann, G. 1999. Endothelin-induced contraction of the portal vein in cirrhosis. Eur. Surg. Res. 31:289–296.PubMedCrossRefGoogle Scholar
  160. Piao, Y. F., He, M., Shi, Y., Tang, T. Y. 2004. Relationship between microvessel density and telomerase activity in hepatocellular carcinoma. World J. Gastroenterol. 10:2147–2149.PubMedGoogle Scholar
  161. Podust, V. N., Fanning, E. 1997. Assembly of functional replication factor C expressed using recombinant baculoviruses. J. Biol. Chem. 272:6303–6310.PubMedCrossRefGoogle Scholar
  162. Purtilo, D. T., Gottlieb, L. S. 1973. Cirrhosis and hepatoma occurring at Boston City Hospital (1917–1968). Cancer 32:458–462.PubMedCrossRefGoogle Scholar
  163. Qadri, I., Conaway, J. W., Conaway, R. C., Schaack, J., Siddiqui, A. 1996. Hepatitis B virus transactivator protein, HBx, associates with the components of TFIIH and stimulates the DNA helicase activity of TFIIH. Proc. Natl. Acad. Sci. U.S.A. 93:10578–10583.PubMedCrossRefGoogle Scholar
  164. Raftogianis, R., Creveling, C., Weinshilboum, R., Weisz, J. 2000. Estrogen metabolism by conjugation. J. Natl. Cancer Inst. Monogr. 2000(27):113–124.CrossRefGoogle Scholar
  165. Ramirez, P., Del Razo, L. M., Gutierrez-Ruiz, M. C., Gonsebatt, M. E. 2000. Arsenite induces DNA–protein crosslinks and cytokeratin expression in the WRL-68 human hepatic cell line. Carcinogenesis 21:701–706.PubMedCrossRefGoogle Scholar
  166. Robinson, W. S. 1994. Molecular events in the pathogenesis of hepadnavirus-associated hepatocellular carcinoma. Annu. Rev. Med. 45:297–323.PubMedCrossRefGoogle Scholar
  167. Rogler, C. E., Sherman, M., Su, C. Y., Shafritz, D. A., Summers, J., Shows, T. B., Henderson, A., Kew, M. 1985. Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma. Science 230:319–322.PubMedCrossRefGoogle Scholar
  168. Roy, D., Liehr, J. G. 1988. Temporary decrease in renal quinone reductase activity induced by chronic administration of estradiol to male Syrian hamsters. J. Biol. Chem. 263:3646–3651.PubMedGoogle Scholar
  169. Schaumloffel, N., Gebel, T. 1998. Heterogeneity of the DNA damage provoked by antimony and arsenic. Mutagenesis 13:281–286.PubMedCrossRefGoogle Scholar
  170. Scorsone, K. A., Zhou, Y. Z., Butel, J. S., Slagle, B. L. 1992. p53 mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res. 52(6):1635–1638.PubMedGoogle Scholar
  171. Sengstag, C. 1997. The molecular mechanism of aflatoxin B1-induced liver cancer: is mitotic recombination involved? Mol. Carcinog. 19:147–152.PubMedCrossRefGoogle Scholar
  172. Sengupta, S., Harris, C. C. 2005. p53: traffic cop at the crossroads of DNA repair and recombination. Nat. Rev. Cell Mol. Biol. 6:44–55.CrossRefGoogle Scholar
  173. Shintani, Y., Hiroshi, Y., Kyoji, M., Hajime, F., Takeya, T., Yumi, K., Satoshi, K., Izumu, S., Kazuhiko, K. 1999. Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system. J. Gen. Virol. 80:3257–3265.PubMedGoogle Scholar
  174. Slagel, B. L., Zhou, Y. -Z., Butel, J. S. 1991. Hepatitis B virus integration event in human chromosome 17p near the p53 gene identifies the region of the chromosome commonly deleted in virus-positive hepatocellular carcinomas. Cancer Res. 51:49–54.Google Scholar
  175. Slaunwhite, W. R., Kirdani, R. Y., Sandberg, A. A. 1973. Metabolic aspects of estrogens in man. In Handbook of physiology, Section 7: endocrinology, Vol II, Part 1. Greep, R. O., Astwood, E. B., Geiger, S. R. eds. American Physiological Society, Washington, DC, pp. 485–523.Google Scholar
  176. Smith, S. J., Li, Y., Whitley, R., Marion, M. J., Partilo, S., Carney, W. P., Brant-Rauf, P. W. 1998. Molecular epidemiology of p53 protein mutations in workers exposed to vinyl chloride. Am. J. Epidemiol. 147(3):302–308.PubMedCrossRefGoogle Scholar
  177. Stack, D., Byun, J., Gross, M. L., Rogan, E. G., Cavalieri, E. 1996. Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides. Chem. Res. Toxicol. 9:851–859.PubMedCrossRefGoogle Scholar
  178. Staib, F., Robles, A. I., Varticovski, L., Wang, X. W., Zeeberg, B. R., Sirotin, M., Zhurkin, V. B., Hofseth, L. J., Hussain, S. P., Weinstein, J. N., Galle, P. R., Harris, C. C. 2005. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res. 65:10255–10264.PubMedCrossRefGoogle Scholar
  179. Swenberg, J. A., Fedtke, N., Ciroussel, F., Barbin, A., Bartsch, H. 1992. Etheno adducts formed in DNA of vinyl chloride-exposed rats are highly persistent in liver. Carcinogenesis 13:727–729.PubMedCrossRefGoogle Scholar
  180. The Collaborative Multicentre International Liver Tumor Study (MILTS) 1997. Oral contraceptives and liver cancer. results of the MILTS study. Contraception 56:275–284.CrossRefGoogle Scholar
  181. Thorgeirsson, S. S., Grisham, J. W. 2002. Molecular pathogenesis of human hepatocellular carcinoma. Nat. Genet. 31:339–346.PubMedCrossRefGoogle Scholar
  182. Tokino, T., Fukushige, S., Nakamura, T., Nagaya, T., Murotsu, T., Shiga, J., Aoki, N., Matsubara, K. 1987. Chromosomal translocation and inverted duplication associated with integrated hepatitis B virus in hepatocellular carcinomas. J. Virol. 61:3848–3854.PubMedGoogle Scholar
  183. Trichopoulos, D., Day, N. E., Kaklamani, E., Tzonou, A., Munoz, N., Zavitsanos, X., Koumantaki, Y., Trichopoulou, A. 1987. Hepatitis B virus, tobacco smoking and ethanol consumption in the etiology of hepatocellular carcinoma. Int. J. Cancer 39:45–49.PubMedCrossRefGoogle Scholar
  184. Trivers, G. E., Cawley, H. L., DeBenedetti, V. M., Hollstein, M., Marion, M. J., Bennett, W. P., Hoover, M. L., Prives, C. C., Tamburro, C. C., Harris, C. C. 1995. Anti-p53 antibodies in sera of workers occupationally exposed to vinyl chloride. J. Natl. Cancer. Inst. 87:1400–1407.PubMedCrossRefGoogle Scholar
  185. Trouba, K. J., Wauson, E. M., Vorce, R. L. 2000. Sodium arseniteinduced dysregulation of proteins involved in proliferative signaling. Toxicol. Appl. Pharmacol. 164:161–170.PubMedCrossRefGoogle Scholar
  186. 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. U.S.A. 87:6791–6794.PubMedCrossRefGoogle Scholar
  187. Urano, Y., Watanabe, K., Lin, C. C., Hino, O., Tamaoki, T. 1991. Interstitial chromosomal deletion within 4q11-q13 in a human hepatoma cell line. Cancer Res. 51:1460–1464.PubMedGoogle Scholar
  188. Vadrot, N., Legrand, A., Nello, E., Bringuier, A. F., Guillot, R., Feldman, G. 2006. Inducible nitric oxide synthase could be responsible for resistance or sensitivity to IFN-gamma-induced apoptosis in several human hepatoma cell lines. J. Interferon Cytokine Res. 26:901–913.PubMedCrossRefGoogle Scholar
  189. Vautier, G., Bomford, A. B., Portmann, B. ,C., Metivier, E., Williams, R. 1999. P53 mutations in British patients with hepatocellular carcinoma: clustering in genetic hemochromatosis. Gastroenterology 117:154–160.PubMedCrossRefGoogle Scholar
  190. Walker, B. E., Kurth, L. A. 1993. Pituitary tumors in mice exposed prenatally to diethylstilbestrol. Cancer Res. 53:1546–1549.PubMedGoogle Scholar
  191. Wang, L. Y., Chen, C. J., Zhang, Y. J., Tsai, W. Y., Lee, P. H., Feitelson, M. A., Lee, C. S., Santella, R. M. 1998. 4-Aminobiphenyl DNA damage in liver tissue of hepatocellular carcinoma patients and controls. Am. J. Epidemiol. 147:315–323.PubMedCrossRefGoogle Scholar
  192. Wang, J., Chenivese, X., Henglein, B., Brechot, C. 1990. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343:555–557.PubMedCrossRefGoogle Scholar
  193. Wang, H. P., Rogler, C. E. 1988. Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas. Cytogenet. Cell Genet. 48:72–78.PubMedCrossRefGoogle Scholar
  194. Wang, L. Y., You, S. L., Lu, S. N., Ho, C. H., Wu, M. H., Sun, C. A., Yang, H. I., Chien-Jen, C. 2003. Risk of hepatocellular carcinoma and habits of alcohol drinking, betel quid chewing and cigarette smoking: a cohort of 2416 HBsAg-seropositive and 9421 HBsAg-seronegative male residents in Taiwan. Cancer Causes Control 14(3):241–250.PubMedCrossRefGoogle Scholar
  195. Weisz, J., Bui, Q. D., Roy, D., Liehr, J. G. 1992. Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: potential pathway of metabolic activation estrogens. Endocrinology 131:655–661.PubMedCrossRefGoogle Scholar
  196. Williams, J., Phillips, T. D., Jolly, P. E., Stiles, J. K., Jolly, C. M., Aggarwal, D. 2004. Human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions. Am. J. Clin. Nutr. 80:1106–1122.PubMedGoogle Scholar
  197. Wilson, S., Jones, L., Coussens, C., and Hanna, K. eds. 2002. Cancer and the environment: gene–environment interactions. The National Academy Press, Washington, DC.Google Scholar
  198. Yu, M. W., Yang, S. Y., Pan, I. J., Lin, C. L., Liu, C. J., Liaw, Y. F., Lin, S. M., Chen, P. J., Lee, S. D., Chen, C. J. 2003. Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma. J. Natl. Cancer Inst. 95:1485–1488.PubMedCrossRefGoogle Scholar
  199. Yu, M. C., Yuan, J. M. 2004. Environmental factors and risk for hepatocellular carcinoma. Gastroentorology 127:S72–S78.CrossRefGoogle Scholar
  200. Yu, M. C., Yuan, J. M., Govindarajan, S., Ross, R. K. 2000. Epidemiology of hepatocellular carcinoma. Can. J. Gastroenterol. 14(8):703–709.PubMedGoogle Scholar
  201. Yu, C. T., Hsu, J. M., Lee, G. Y. C., Tsou, A. P., Chou, C. K., Huang, F. C. Y. 2005. Phosphorylation and stabilization of HURP by Aurora-A: implication of HURP as a transforming target of Aurora-A. Mol. Cell Biol. 25:5789–5800.PubMedCrossRefGoogle Scholar
  202. Yuan, J. M., Govindarajan, S., Arakawa, K., Yu, M. C. 2004. Synergism of alcohol, diabetes and viral hepatitis on risk of hepatocellular carcinoma in US blacks and whites. Cancer 101:1009–1017.PubMedCrossRefGoogle Scholar
  203. Zhao, C. Q., Young, M. R., Diwan, B. A., Coogan, T. P., Waalkes, M. P. 1997. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc. Natl. Acad. Sci. U.S.A. 94:10907–10912.PubMedCrossRefGoogle Scholar
  204. Zhou, Y. S., Zhou, D. X., Zhu, S. L., Jin, D. X., Peng, J. H., Huang, S. Q. 1994. Investigation of arsenic content in food dried by normal coal and high arsenic-containing coal. Chin. Public Health 10:77–79.Google Scholar

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  1. 1.Sanofi-Aventis PharmaceuticalsRegulatory Pharmacology and Toxicology – USBridgewaterUSA

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