Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Molecular pathogenesis of human hepatocellular carcinoma

Nature Genetics volume 31, pages 339–346 (2002)Cite this article

Abstract

Hepatocarcinogenesis is a slow process during which genomic changes progressively alter the hepatocellular phenotype to produce cellular intermediates that evolve into hepatocellular carcinoma. During the long preneoplastic stage, in which the liver is often the site of chronic hepatitis, cirrhosis, or both, hepatocyte cycling is accelerated by upregulation of mitogenic pathways, in part through epigenetic mechanisms. This leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomere erosion and telomerase re-expression, sometimes microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and emergence of hepatocellular carcinoma are associated with the accumulation of irreversible structural alterations in genes and chromosomes, but the genomic basis of the malignant phenotype is heterogeneous. The malignant hepatocyte phenotype may be produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of hepatocellular carcinoma. New strategies should enable these variants to be characterized.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: Changes in expression of TGF-α and IGF-2, monoclonality and cell cycling in hepatocytes from livers that were the site of chronic hepatitis (yellow) and cirrhosis (green), in dysplastic hepatocytes (blue) and in HCC (red).
Figure 3: Changes in telomerase expression, aberrant gene methylation, microsatellite instability and fraction of alleles deleted in hepatocytes from livers the site of chronic hepatitis (yellow) and cirrhosis (green), dysplastic hepatocytes (blue) and HCC (red).
Figure 4: Autosome arms that contain allelic deletions in more than 30% of reported HCC.
Figure 5: Autosome arms that show regional losses (red) and gains (green) in more than 20% of reported HCC, as detected by comparative genomic hybridization.
Figure 6
Figure 7: Accumulation of selected structural genomic aberrations in HCC with progressive deterioration of tumor cell differentiation.

Similar content being viewed by others

References

  1. Ferlay, J., Bray, F., Pisani, P. & Parkin, D.M.J. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0., IARC CancerBase No. 5 (Lyon, IARC Press, 2001).

  2. Parkin, D.M., Bray, F.I. & Devesa, S.S. Cancer burden in the year 2000. The global picture. Eur. J. Cancer 37, S4–S66 (2001).

    Article  PubMed  Google Scholar 

  3. Grisham, J.W. Molecular genetic alterations in primary hepatocellular neoplasms: hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma. In The Molecular Basis of Human Cancer (eds Coleman, W.B. & Tsongalis, G.J.) 269–346 (Humana Press, Totowa, New Jersey, 2001).

    Google Scholar 

  4. Bosch, F.X., Ribes, J. & Borràs, J. Epidemiology of primary liver cancer. Semin. Liver Dis. 19, 271–285 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Buendia, M.A. Genetics of hepatocellular carcinoma. Semin. Cancer Biol. 10, 185–200 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Bréchot, C. Molecular mechanisms of hepatitis B and C related to liver carcinogenesis. Hepatogastroenterology 45 (Suppl 3), 1189–1196 (1998).

    PubMed  Google Scholar 

  7. Diao, J., Garces, R. & Richardson, C.D. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis (Survey). Cytokine Growth Factor Rev. 12, 189–205 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Smela, M.E., Currier, S.S., Bailey, E.A. & Essigmann, J.M. The chemistry and biology of aflatoxin B1: from mutational spectrometry to carcinogenesis. Carcinogenesis 22, 535–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Tong, M.J., El-Farra, N.S., Reikes, A.R. & Co, R.L. Clinical outcomes after transfusion-associated hepatitis C. New Engl. J. Med. 332, 1463–1466 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Takano, S., Yokosuka, O., Imazeki, F., Tagawa, M. & Omata, M. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients. Hepatology 21, 650–655 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Chu, C.M. Natural history of chronic hepatitis B infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma. J. Gastroenterol. Hepatol. 15 (Suppl) E25–E30 (2000).

    Article  PubMed  Google Scholar 

  12. Oka, H. et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 12, 680–687 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. Ikeda, K. et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18, 47–53 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Kato, Y. et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses. Cancer 74, 2234–2238 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. del Olmo, J.A. et al. Incidence and risk factors for hepatocellular carcinoma in 967 patients with cirrhosis. J. Cancer Res. Clin. Oncol. 124, 560–564 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Chiaramonte, M. et al. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85, 2132–2137 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Takayama, T. et al. Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet 336, 1150–1153 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Seki S. et al. Outcomes of dysplastic nodules in human cirrhotic liver: a clinicopathological study. Clin. Cancer Res. 6, 3469–3473 (2000).

    CAS  PubMed  Google Scholar 

  19. Kawakita, N. et al. Analysis of proliferating hepatocytes using a monoclonal antibody against proliferating cell nuclear antigen/cyclin in embedded tissues from various liver diseases fixed in formaldehyde. Am. J. Pathol. 140, 513–520 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Schwienbacher, C. et al. Gain of imprinting at chromosome 11p15: a pathogenetic mechanism identified in human hepatocarcinoma. Proc. Natl Acad. Sci. USA 97, 5445–5449 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Soini, Y., Virkajärvi, N., Lehto, V.P. & Pääkkö, P. Hepatocellular carcinoma with a high proliferative index and a low degree of apoptosis and necrosis are associated with a shortened survival. Br. J. Cancer 73, 1025–1030 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Theise, N.D. et al. Low proliferative activity in macroregenerative nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis. Liver 16, 134–139 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Paradis, V., Laurendeau. I., Vidaud, M. & Bedossa, P. Clonal analysis of macronodules in cirrhosis. Hepatology 28, 953–958 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Ochai, T., Urata, Y., Yamano, T., Yamagishi, H. & Ashihara, T. Clonal expansion in evolution of chronic hepatitis to hepatocellular carcinoma as seen at an X-chromosome locus. Hepatology 31, 615–621 (2000).

    Article  Google Scholar 

  25. Paradis, V. et al. Clonal analysis of micronodules in virus C-induced liver cirrhosis using laser capture microdissection (LCM) and HUMARA assay. Lab. Invest. 80, 1553–1559 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Okuda, T. et al. Clonal analysis of hepatocellular carcinoma and dysplastic nodule by methylation pattern of X-chromosome-linked human androgen receptor gene. Cancer Lett. 164, 91–96 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Kitamoto, M. & Ide, T. Telomerase activity in precancerous hepatic nodules. Cancer 85, 245–248 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Takaishi, H. et al. Precancerous hepatic nodules had significant levels of telomerase activity determined by sensitive quantitation using hybridization protection assay. Cancer 88, 312–317 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Toshikuni, N. et al. Expression of telomerase-associated protein 1 and telomerase reverse transcriptase in hepatocellular carcinoma. Br. J. Cancer 82, 833–837 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu, Y.W., Chang, K.J. & Liu, Y.C. DNA hypomethylation of proliferating cell nuclear antigen gene in human hepatocellular carcinoma is not due to cell proliferation. Cancer Lett. 70, 189–196 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Shen, L. et al. Correlation between DNA methylation and pathological changes in human hepatocellular carcinoma. Hepatogastroenterology 45, 1753–1759 (1998).

    CAS  PubMed  Google Scholar 

  32. Kanai, Y. et al. DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology 29, 703–709 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Nagai, H. et al. A novel sperm-specific hypomethylation sequence is a demethylation hotspot in human hepatocellular carcinoma. Gene 237, 15–20 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Kanai, Y., Ushijima, S., Tsuda, H., Sakamoto, M. & Hirohashi, S. Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis. Cancer Lett. 148, 73–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. JinBaek, M. et al. p16 is a major inactivation target in hepatocellular carcinoma. Cancer 89, 60–68 (2000).

    Article  Google Scholar 

  36. Kondo, Y. et al. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis—a comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology 32, 970–979 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Takai, D., Yagi, Y., Habib, N., Sugimura, T. & Ushijima, T. Hypomethylation of LINE1 retrotransposon in human hepatocellular carcinomas, but not in surrounding liver cirrhosis. Jpn. J. Clin. Oncol. 30, 306–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Tchou, J.C. et al. GSTP1 CpG island DNA hypermethylation in hepatocellular carcinoma. Int. J. Oncol. 16, 663–676 (2000).

    CAS  PubMed  Google Scholar 

  39. Kaneto, H. et al. Detection of hypermethylation of the p16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus. Gut 48, 372–377 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lin, C.H. et al. Genome-wide hypomethylation in hepatocellular carcinogenesis. Cancer Res. 61, 4238–4243 (2001).

    CAS  PubMed  Google Scholar 

  41. Saito, Y. et al. Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology 33, 561–568 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Karachristos, A. et al. Microsatellite instability and p53 mutations in hepatocellular carcinoma. Mol. Cell Biol. Res. Commun. 2, 155–161 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Kawai, H. et al. Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology 31, 1246–1250 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Maggioni, M. et al. Molecular changes in hepatocellular dysplastic nodules on microdissected liver biopsies. Hepatology 32, 942–946 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Park, Y.M. et al. Microsatellite instability and mutations of E2F-4 in hepatocellular carcinoma from Korea. Hepatol. Res. 17, 102–111 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Piao, Z., Kim, H., Malkhosyan, S. & Park, C. Frequent chromosomal instability but no microsatellite instability in hepatocellular carcinomas. Int. J. Oncol. 17, 507–512 (2000).

    CAS  PubMed  Google Scholar 

  47. Roncalli, M. et al. Fractional allelic loss in non-end-stage cirrhosis: correlations with hepatocellular carcinoma development during follow-up. Hepatology 31, 846–850 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Saeki, A. et al. Lack of frameshift mutations at coding mononucleotide repeats in hepatocellular carcinoma in Japanese patients. Cancer 88, 1025–1029 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Sun, M. et al. An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region. Hepatology 33, 1415–1424 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, T.C. et al. p16INK4 gene mutation and allelic loss of chromosome 9p21-22 in Taiwanese hepatocellular carcinoma. Anticancer Res. 20, 1621–1626 (2000).

    CAS  PubMed  Google Scholar 

  51. Okabe, H. et al. 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 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Chen, Y.J. et al. Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma. Gastroenterology 119, 431–440 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Guan, X.Y. et al. Recurrent chromosome alterations in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 29, 110–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Marchio, A. et al. Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients. Oncogene 19, 3733–3738 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Tornillo, L. et al. Marked genetic similarities between hepatitis B virus-positive and hepatitis C virus-positive hepatocellular carcinomas. J. Pathol. 192, 307–312 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Wong, N. et al. Genomic aberrations in human hepatocellular carcinomas of differing etiologies. Clin. Cancer Res. 6, 4000–4009 (2000).

    CAS  PubMed  Google Scholar 

  57. Zondervan, P.E. et al. Molecular cytogenetic evaluation of virus-associated and non-viral hepatocellular carcinoma: analysis of 26 carcinomas and 12 concurrent dysplasias. J. Pathol. 192, 207–215 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Balsara, B.R. et al. Human hepatocellular carcinoma is characterized by a highly consistent pattern of genomic imbalances, including frequent loss of 16q23.1-24.1. Genes Chromosomes Cancer 30, 245–253 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Rao, U.N. et al. Comparative genomic hybridization of hepatocellular carcinoma: correlation with fluorescence in situ hybridization in paraffin-embedded tissue. Mol. Diagn. 6, 27–37 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Wilkens, L. et al. Differentiation of liver cell adenomas from well-differentiated hepatocellular carcinomas by comparative genomic hybridization. J. Pathol. 193, 476–482 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Laes, J. et al. Alterations in P19ARF in rodent hepatoma cell lines but not in human primary liver cancer. Cancer Genet. Cytogenet. 117, 118–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Wong, N. et al. A comprehensive karyotype study of human hepatocellular carcinoma by spectral karyotyping. Hepatology 32, 1060–1068 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Strauss, B.S. Frameshift mutation, microsatellites, and mismatch repair. Mutat. Res. 437, 195–203 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Loeb, L.A. A mutator phenotype in cancer. Cancer Res. 61, 3230–3239 (2001).

    CAS  PubMed  Google Scholar 

  65. Stewart, S.A. & Weinberg, R.A. Telomerase and human tumorigenesis. Semin. Cancer Biol. 10, 399–406 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Kane, J.M. III et al. Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis. J. Surg. Res. 69, 321–324 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Hussain, S.P. et al. Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: oxyradical overload diseases. Proc. Natl Acad. Sci. USA 97, 12770–12775 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nishikawa, M. et al. Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma. Cancer Res. 61, 1843–1845 (2001).

    CAS  PubMed  Google Scholar 

  69. Yamamoto, H. et al. Infrequent widespread microsatellite instability in hepatocellular carcinoma and non-HCC tissues. Oncology Rep. 7, 725–729 (2000).

    Google Scholar 

  70. Shi, C.Y. et al. Codon 249 mutation of the p53 gene is a rare event in hepatocellular carcinomas from ethnic Chinese in Singapore. Br. J. Cancer 72, 146–149 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Terris, B. et al. Close correlation between β-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 18, 6583–6588 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Hsu, H.C. et al. β-Catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am. J. Pathol. 157, 763–770 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Satoh, S. et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 24, 245–250 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Stern, M.C. et al. Hepatitis B, aflatoxin B1, and p53 codon 249 mutation in hepatocellular carcinomas from Guangxi, People's Republic of China, and a meta-analysis of existing studies. Cancer Epidemiol. Biomarkers Prev. 10, 617–625 (2001).

    CAS  PubMed  Google Scholar 

  75. Mao, T.L., Chu, J.S., Jeng, Y.M., Lai, P.L. & Hsu, H.C. Expression of mutant nuclear βcatenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis. J. Pathol. 193, 95–101 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Wilkens, L., Bredt, M., Flemming, P., Klempnauer, J. & Heinrich Kreipe, H. Differentiation of multicentric origin from intra-organ metastatic spread of hepatocellular carcinomas by comparative genomic hybridization. J. Pathol. 192, 43–51 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. van Oijen, M.G. & Slootweg, P.J. Oral field cancerization: carcinogen-induced independent events or micrometastastic deposits? Cancer Epidemiol. Biomarkers Prev. 9, 249–256 (2000).

    CAS  PubMed  Google Scholar 

  78. Ng, I.O., Liang, Z.D., Cao, L. & Lee, T.K. DLC-1 is deleted in primary hepatocellular carcinoma and exerts inhibitory effects on the proliferation of hepatoma cell lines with deleted DLC-1. Cancer Res. 60, 6581–6584 (2000).

    CAS  PubMed  Google Scholar 

  79. Emmert-Buck, M.R. et al. Laser capture microdissection. Science 274, 998–1001 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. Tao, L.C. Oral contraceptive–associated liver cell adenoma and hepatocellular carcinoma. Cytomorphology and mechanism of malignant transformation. Cancer 68, 341–347 (1991).

    Article  CAS  PubMed  Google Scholar 

  81. Liotta, L. & Petricoin, E. Molecular profiling of human cancer. Nature Rev. Genet. 1, 48–56 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Hsu, H.C., Cheng, W. & Lai, P.L. Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. Cancer Res. 57, 5179–5184 (1997).

    CAS  PubMed  Google Scholar 

  83. Lau, W.Y. et al. Differential gene expression of hepatocellular carcinoma using cDNA microarray analysis. Oncol. Res. 12, 59–69 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Honda, M., Kaneko, S., Kawai, H., Shirota, Y. & Kobayashi, K. Differential gene expression between chronic hepatitis B and C hepatic lesion. Gastroenterology 120, 955–966 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Lu, T. et al. Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol. Sci. 59, 185–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Okabe, H. et al. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res. 61, 2129–2137 (2001).

    CAS  PubMed  Google Scholar 

  87. Shirota, Y., Kaneko, S., Honda, M., Kawai, H.F. & Kobayashi, K. Identification of differentially expressed genes in hepatocellular carcinoma with cDNA microarrays. Hepatology 33, 832–840 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Xu, L. et al. Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma. Cancer Res. 61, 3176–3181 (2001).

    CAS  PubMed  Google Scholar 

  89. Yamashita, T. et al. Serial analysis of gene expression in chronic hepatitis C and hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 282, 647–654 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Pollack, J.R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat. Genet. 23, 41–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Lindblad-Toh, K. et al. Loss of heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat. Biotechnol. 18, 1001–1005 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Risch, N.J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Grisham, J.W. Interspecies comparison of liver carcinogenesis: implications for cancer risk assessment. Carcinogenesis 18, 59–81 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Kemp, C.J. Comparative hepatocellular cancer genetics. Am. J. Pathol. 154, 975–977 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fausto, N. Mouse liver tumorigenesis: models, mechanisms, and relevance to human disease. Semin. Liver Dis. 19, 243–252 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Thorgeirsson, S.S., Factor, V.M. & Snyderwine, E.G. Transgenic mouse models in carcinogenesis research and testing. Toxicol. Lett. 112–113, 553–555 (2000).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Snorri S. Thorgeirsson & Joe W. Grisham

  2. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, USA, North Carolina

    Joe W. Grisham

Authors
  1. Snorri S. Thorgeirsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joe W. Grisham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Snorri S. Thorgeirsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thorgeirsson, S., Grisham, J. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31, 339–346 (2002). https://doi.org/10.1038/ng0802-339

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0802-339

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing