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Hepatocellular carcinoma and hepatitis B virus infection: molecular evidence for monoclonal origin and expansion of malignantly transformed hepatocytes

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  • Clinical Oncology or Epidemiology
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Summary

The clonality of tumor cells was studied in a patient with metastasizing hepatocellular carcinoma (HCC). Using hepatitis B virus (HBV) DNA as a genetic marker, the pattern of integration of viral DNA into the tumor cell genome was determined by Southern blot analyses of DNAs extracted from different HCC lesions in the liver and both lungs. All tumor tissues examined were found to have viral DNA integrated into the same site(s) of the cellular genome. This finding provides direct molecular evidence for a monoclonal origin and expansion of malignantly transformed hepatocytes during tumor growth and metastasis. This characteristic is similar to other human cancers associated with viral infections, such as adult T-cell leukemia, Burkitt's lymphoma, or cervical cancer, and is important für our understanding of viral oncogenesis in man.

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References

  • Beasley RP, Hwang LY, Lin CC, Chen CS (1981) Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet II:1129–1132

    Article  Google Scholar 

  • Blum HE, Haase AT, Harris JD, Walker D, Vyas GN (1984a) Asymmetric metric replication of hepatitis B virus DNA in human liver: demonstration of cytoplasmic minus-strand DNA by blot analyses and in situ hybridization. Virology 139:87–96

    Article  PubMed  Google Scholar 

  • Blum HE, Haase AT, Vyas GN (1984b) Molecular pathogenesis of hepatitis B virus infection: simultaneous detection of viral DNA and antigens in paraffin-embedded liver sections. Lancet II:771–775

    Article  Google Scholar 

  • Blum HE, offensperger W-B, Walter E, offensperger S, Zeschnigk C, Wahl A, Gerok W (1987) Extrachromosomal hepatitis B virus DNA in hepatitis B surface antigen-negative liver disease. N Engl J Med (in press)

  • Brechot C, Pourcel C, Louise A, Rain B, Tiollais P (1980) Presence of integrated hepatitis B virus sequences in cellular DNA of human hepatocellular carcinoma. Nature 286:533–535

    PubMed  Google Scholar 

  • Brechot C, Hadchouel M, Scotto J, Fonck M, Potet F, Vyas GN, Tiollais P (1981) State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and-negative liver diseases. Proc Natl Acad Sci USA 78:3906–3910

    PubMed  Google Scholar 

  • Chakraborty PR, Ruiz-Opazo N, Shouval D, Shafritz DA (1980) Identification of integrated hepatitis B virus DNA and expression of viral RNA in an HBsAg-producing human hepatocellular carcinoma cell line. Nature 286:531–533

    PubMed  Google Scholar 

  • Cummings IW, Brown JK, Salser W, Tyler GV, Snyder RL, Smolec JM, Summers J (1980) Isolation, characterization and comparison of recombinant DNA-derived genomes of human hepatitis B virus and woodchuck hepatitis virus. Proc Natl Acad Sci USA 77:1842–1846

    PubMed  Google Scholar 

  • Dejean A, Brechot C, tiollais P, Wain-Hobson S (1983) Characterization of integrated hepatitis B viral DNa cloned from a human hepatoma and the hepatoma cell line PLC/PRF/5. Proc Natl Acad Sci USA 80:2505–2509

    PubMed  Google Scholar 

  • Dejean A, Bougueleret L, Grzeschik K-H, 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 322:70–72

    PubMed  Google Scholar 

  • Edman JC, Gray P, Valenzuela P, Rall LB, Rutter WJ (1980) Integration of hepatitis B virus sequences and their expression in a human hepatoma cell. Nature 286:535–538

    PubMed  Google Scholar 

  • Esumi M, Aritaka T, Arii M, Suzuki K, Tanikawa K, Mizuo H, Mima T, Shikata T (1986) Clonal origin of human hepatoma determined by integration of hepatitis B virus DNA. Cancer Res 46:5767–5771

    PubMed  Google Scholar 

  • Fowler MJF, Greenfield C, Chu C-M, Karayiannis P, Dunk A, Lok ASF, Lai CL, Yeoh EK, Monjardino JP, Wankya BM, Thomas HC (1986) Integration of HBV DNA may not be a prerequisite for the maintenance of the state of malignant transformation. An analysis of 110 liver biopsies. J Hepatol 2:218–229

    PubMed  Google Scholar 

  • Galloway DA, McDougall JK (1983) The oncogenic potential of herpes simplex viruses: evidence for a hit-and-run mechanism. Nature 302:21–24

    PubMed  Google Scholar 

  • Henle W, Henle G (1979) The Epstein-Barr virus. Springer, Berlin Heidelberg New York

    Google Scholar 

  • Hino O, Kitagawa T, Koike K, Kobayashi M, Hara M, Mori W, Nakashima T, Hattori N, Sugano H (1984) Detection of hepatitis B virus DNA in hepatocellular carcinoma in Japan. Hepatology 4:90–95

    PubMed  Google Scholar 

  • Hino O, Kitagawa T, Sugano H (1985) Relationship between serum and histochemical markers for hepatitis B virus and rate of viral integration in hepatocellular carcinoma in Japan. Int J Cancer 35:5–10

    PubMed  Google Scholar 

  • Imazeki F, Omata M, Yokosuka O, Okuda K (1986) Integration of hepatitis B virus DNA in hepatocellular carcinoma. Cancer 58:1055–1060

    PubMed  Google Scholar 

  • Itakura K, Hirose T, Crea R, Riggs AD, Heynecker HL, Bolivar F, Boyer HW (1977) Experssion in Escherichia coli of a chemically synthesized gene for the human somatostatin. Science 198:1056–1063

    PubMed  Google Scholar 

  • Kew MC (1984) The possible etiologic role of hepatitis B virus in hepatocellular carcinoma: evidence from southern Africa. In: Chisari FV (ed) Advances in hepatitis research. Masson, New York, pp 203–215

    Google Scholar 

  • Knudson AG jr (1983) Hereditary cancers in man. Cancer Invest 1:187–193

    PubMed  Google Scholar 

  • Koshy R, Koch S, Freytag von Loringhoven A, Kahmann R, Murray K, Hofschneider P (1983) Integration of hepatitis B virus DNA: evidence for integration in the single-stranded gap. Cell 34:215–223

    Article  PubMed  Google Scholar 

  • Lehn H, Krieg P, Sauer G (1985) Paplllomavirus genomes in human cervical tumors: analysis of their transcriptional activity. Proc Natl Acad Sci USA 82:5540–5544

    PubMed  Google Scholar 

  • Maniatis T, Fritsch GF, Sambrook J (1982) Molecular cloning. A laboratory manual. Cold Spring Harbor Laboratory. Cold Spring Harbor, New York

    Google Scholar 

  • Miyaki M, Sato C, Gotanda T (1986) Integration of region X of hepatitis B virus genome in human primary hepatocellular carcinomas propagated in nude mice. J Gen Virol 67:1449–1454

    PubMed  Google Scholar 

  • Möröy T, Marchio A, Etiemble J, Trepo C, Tiollais P, Buendia M-A (1986) Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature 324:276–279

    PubMed  Google Scholar 

  • Popper H (1986) The relation between hepatitis B virus infection and hepatocellular carcinoma. Hepatogastroenterology 33:2–5

    PubMed  Google Scholar 

  • Rigby PWJ, Dieckmann M, Rhodes C, Berg P (1977) Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase. I. J Mol Biol 113:237–251

    PubMed  Google Scholar 

  • Robinson WS, Miller RH, Klote L, Marion PL, Lee S-C (1984) Hepatitis B virus and hepatocellular carcinoma. In: Vyas GN, Hoofnagle JH, Dienstag JL (eds) Viral hepatitis and liver diseases. Grune and Stratton, Orlando, pp 245–263

    Google Scholar 

  • Rogler CE, Sherman M, Su CY, Shafitz DA, Summers J, Shows TB, Henderson A, Kew MC (1985) Deletion of chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma. Science 230:319–322

    PubMed  Google Scholar 

  • Shafritz DA, Lieberman HM (1984) The molecular biology of hepatitis B virus. Ann Rev Med 35:219–232

    Article  PubMed  Google Scholar 

  • Shafritz DA, Shouval D, Sherman HI, Hadziyannis SI, Kew MC (1981) Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. N Engl J Med 301:1067–1073

    Google Scholar 

  • Stanbridge EJ (1984) Genetic analysis of tumorigenicity in human cell hybrids. Cancer Surveys 3:335–350

    Google Scholar 

  • Stanbridge EJ, Der CJ, Doersen CJ, Nishimi RY, Peehl DM, Weissman BE, Wilkinson J (1982) Human cell hybrids: analysis of transformation and tumorigenicity. Science 215:252–259

    PubMed  Google Scholar 

  • Standring DN, Rutter WJ (1986) The molecular analysis of hepatitis B virus. Prog Liver Dis 8:311–333

    PubMed  Google Scholar 

  • Sternberger LA (1979) Immunocytochemistry. Wiley, New York

    Google Scholar 

  • Szmuness W (1978) Hepatocellular carcinoma and hepatitis B virus: evidence for a causal relationship. Prog Med Virol 24:40–69

    PubMed  Google Scholar 

  • tiollais P, Pourcel C Dejean A (1985) The hepatitis B virus. Nature 317:489–495

    PubMed  Google Scholar 

  • Twist ME, Clark HF, Aden DP, Knowles BB, Plotkin SA (1981) Integration pattern of hepatitis B virus DNA sequences in human hepatoma cell lines. J Virol 37:239–243

    PubMed  Google Scholar 

  • Valenzuela P, Quiroga M, Zaldivar J, Gray P, Rutter WJ (1980) The nucleotide sequence of the hepatitis B viral genome and the identification of the major viral genes. In: Fields B, Jaenisch R, Fox CF (eds) Animal virus genetics. Academic Press, New York, pp 57–70

    Google Scholar 

  • Varmus HE (1984) Do hepatitis viruses make a genetic contribution to primary hepatocellular carcinoma? In: Vyas GN, Hoofnagle JH, Dienstag JL (eds) Viral hepatitis and liver disease. Grune and Stratton, Orlando, pp 411–414

    Google Scholar 

  • Vogelstein B, Gillespie I (1979) Preparative and analytical purification of DNA from agarose. Proc Natl Acad Sci USA 76:615–619

    PubMed  Google Scholar 

  • Walter E, Blum HE, offensperger W-B, Zeschnigk C, offensperger S, Gerok W (1987) Spot-blot hybridization assay for the detection of HBV DNA in serum: factors determining its sensitivity and specificity. Hepatology 7:557–562

    PubMed  Google Scholar 

  • zur Hausen H (1980) The role of viruses in human cancers. Adv Cancer Res 33:77–107

    PubMed  Google Scholar 

  • zur Hausen H (1986) Intracellular surveillance of persisting viral infections. Human genital cancer results from deficient control of papillomavirus gene expression. Lancet II:489–491

    Article  Google Scholar 

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Blum, H.E., offensperger, W.B., Walter, E. et al. Hepatocellular carcinoma and hepatitis B virus infection: molecular evidence for monoclonal origin and expansion of malignantly transformed hepatocytes. J Cancer Res Clin Oncol 113, 466–472 (1987). https://doi.org/10.1007/BF00390041

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  • DOI: https://doi.org/10.1007/BF00390041

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