Chromosomal aberrations in human hepatocellular carcinomas associated with hepatitis C virus infection detected by comparative genomic hybridization

Article metrics

Summary

Thirty-five hepatocellular carcinomas (HCCs) associated with hepatitis C virus (HCV) were analysed by comparative genomic hybridization (CGH), to screen for changes in copy-number of DNA sequences. Chromosomal losses were noted in 1p34–36 (37%), 4q12–21 (48%), 5q13–21 (35%), 6q13–16 (23%), 8p21–23 (28%), 13q (20%), 16q (33%) and 17p13 (37%). Gains were noted in 1q (46%), 6p (20%), 8q21–24 (31%) and 17q (43%). High level gains indicative of gene amplifications were found in 7q31 (3%), 11q13 (3%), 14q12 (6%) and 17q12 (3%); amplification at 14q12 may be characteristic for HCCs. No significant difference in chromosomal aberrations was noted between carcinomas associated with HCV-infection in our study and those reported earlier in HCCs infected with hepatitis B virus (HBV), indicating that both HBV- and HCV-related carcinomas may progress through a similar cascade of molecular events.

Change history

  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  1. Ariyama, Y., Fukuda, Y., Okuno, Y., Seto, M., Date, K., Abe, T., Nakamura, Y. & Inazawa, J. (1998). Amplification on double-minute chromosomes and partial-tandem duplication of the MLL gene in leukemic cells of a patient with acute myelogenous leukemia. Genes Chromosomes Cancer 23: 267–272.

  2. Borg, A., Zhang, Q. X., Olsson, H. & Wenngren, E. (1992). Chromosome 1 alterations in breast cancer: allelic loss on 1p and 1q is related to lymphogenic metastases and poor prognosis. Genes Chromosomes Cancer 5: 311–320.

  3. Buetow, K. H., Murray, J. C., Israel, J. L., London, W. T., Smith, M., Kew, 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: 8852–8856.

  4. Cano, J., Oliveros, O. & Yunis, E. (1994). Phenotype of variants malignancy, additional copies of 6p in retinoblastoma. Cancer Genet Cytogenet 76: 112–115.

  5. Di Biscegli, A. M. (1997). Hepatitis C and hepatocellular carcinoma. Hepatology 26: 34S–38S.

  6. Emi, M., Fujiwara, Y., Ohata, H., Tsuda, H., Hirohashi, S., Koike, M., Miyaki, M., Monden, M. & Nakamura, Y. (1993). Allelic loss at chromosome band 8p21.3–p22 is associated with progression of hepatocellular carcinoma. Genes Chromosomes Cancer 7: 152–157.

  7. Fong, T. L., Shindo, M., Feinstone, S. M., Hoofnagle, J. H. & Di Bisceglie, A. M. (1991). Detection of replicative intermediates of hepatitis C viral RNA in liver and serum of patients with chronic hepatitis C. J Clin Invest 88: 1058–1060.

  8. Forus, A., Weghuis, D. O., Smeets, D., Fodstad, O., Myklebost, O. & Geurts Van Kessel, A. (1995). Comparative genomic hybridization analysis of human sarcomas: II. Identification of novel amplicons at 6p and 17p in osteosarcomas. Genes Chromosomes Cancer 14: 15–21.

  9. Fourel, G. (1994). Genetic and epigenetic alterations of gene expression in the course of hepatocarcinogenesis. In Liver Gene Expression, Tronche F and Moshe Y (eds), pp. 298–343. R.G. Landes: Austin, TX

  10. Fujimori, M., Tokino, T., Hino, O., Kitagawa, T., Imamura, T., Okamoto, E., Mitsunobu, M., Ishikawa, T., Nakagawa, H., Hayada, H., Yagura, M., Matsubara, K. & Nakamura, Y. (1991). Allotype study of primary hepatocellular carcinoma. Cancer Res 51: 89–93.

  11. Fujimoto, Y., Hampton, L. L., Wirth, P. J., Wang, N. J., Xie, J. P. & Thorgeirsson, S. S. (1994). Alteration of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China. Cancer Res 54: 281–285.

  12. Fujiwara, Y., Ohata, H., Emi, M., Okui, K., Koyama, K., Tsuchiya, E., Nakajima, T., Monden, M., Mori, T., Kurimasa, A., Oshimura, M. & Nakamura, Y. (1994). A 3-Mb physical map of the chromosome region 8p21.3–p22, including a 600-kb region commonly deleted in human hepatocellular carcinoma, colorectal cancer, and non-small cell lung cancer. Genes Chromosomes Cancer 10: 7–14.

  13. Kaghad, M., Bonnet, H., Yang, A., Creancier, L., Biscan, J. C., Valent, A., Minty, A., Chalon, P., Lelias, J. M., Dumont, X., Ferrara, P., McKeon, F. & Caput, D. (1997). Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90: 809–819.

  14. Kallioniemi, A., Kallioniemi, O. P., Sudar, D., Rutovitz, D., Gray, J. W., Waldman, F. & Pinkel, D. (1992). Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258: 818–820.

  15. Kallioniemi, A., Kallioniemi, O-P, Piper, J., Tanner, M., Stokke, T., Chen, L., Smith, H. S., Pinkel, D., Gray, J. W. & Waldman, F. M. (1994). Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc Natl Acad Sci USA 91: 2156–2160.

  16. Kameda, T., Yasui, W., Yoshida, K., Tsujino, T., Nakayama, H., Ito, M., Ito, H. & Tahara, E. (1990). Expression of ERBB2 in human gastric carcinomas; relationship between p185ERBB2 and the gene amplification. Cancer Res 15: 8002–8009.

  17. Kasai, Y., Takeda, S. & Takagi, H. (1996). Pathogenesis of hepatocellular carcinoma: a review from the viewpoint of molecular analysis. Semin Surg Oncol 12: 155–159.

  18. Knuutila, S., Bjorkqvist, A. M., Autio, K., Tarkkanen, M., Wolf, M., Monni, O., Szymanska, J., Larramendy, M. L., Tapper, J., Pere, H., El-Rifai, W., Hemmer, S., Wasenius, V. M., Vidgren, V. & Zhu, Y. (1998). DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am J Pathol 152: 1107–1123.

  19. Kruh, G. D., Perego, R., Miki, T. & Aaronson, S. A. (1990). The complete coding sequence of arg defines the Abelson subfamily of cytoplasmic tyrosine kinases. Proc Natl Acad Sci USA 87: 5802–5806.

  20. Kuroki, T., Fujiwara, Y., Tsuchiya, E., Nakamori, S., Imaoka, S., Kanematsu, T. & Nakamura, Y. (1995). Accumulation of genetic changes during development of and progression of hepatocellular carcinoma: Loss of heterozygosity on chromosome arm 1p occurs at early stage of hepatocarcinogenesis. Genes Chromosomes Cancer 13: 163–167.

  21. Lowichik, A., Schneider, N. R., Tonk, V., Ansari, M. Q. & Timmons, C. F. (1996). Report of a complex karyotype in recurrent metastatic fibrolamellar hepatocellular carcinoma and a review of hepatocellular carcinoma cytogenetics. Cancer Genet Cytogenet 88: 170–174.

  22. Marchio, A., Meddeb, M., Pineau, P., Danglot, G., Tiollais, P., Bernheim, A. & Dejean, A. (1997). Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 18: 59–65.

  23. Moroy, 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.

  24. Nagai, H., Pineau, P., Tiollais, P., Buendia, M. A. & Dejean, A. (1997). Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene 14: 2927–2933.

  25. Nalpas, B., Driss, F., Pol, S., Hamelin, B., Housset, C., Brechot, C. & Berthelot, P. (1991). Association between HCV and HBV infection in hepatocellular carcinoma and alcoholic liver disease. J Hepatol 12: 70–74.

  26. Nishida, N., Fukuda, Y., Ishizaki, K. & Nakao, K. (1997). Alteration of cell cycle-related genes in hepatocarcinogenesis. Histol Histopathol 12: 1019–1025.

  27. Oda, T., Tsuda, H., Scarpa, A., Sakamoto, M. & Hirahashi, S. (1992). P53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res 52: 6358–6364.

  28. Rogler, C. E. & Chisari, F. V. (1992). Cellular and molecular mechanisms of hepatocarcinogenesis. Semin Liver Dis 12: 265–278.

  29. Sakakura, C., Mori, T., Sakabe, T., Ariyama, Y., Shinomiya, T., Date, K., Hagiwara, A., Yamaguchi, T., Takahashi, T., Nakamura, Y., Abe, T. & Inazawa, J. (1999). Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization. Genes Chromosomes Cancer 24: 299–305.

  30. Schaapveld, R. Q., Van Den Maagdenberg, A. M., Schepens, J. T., Weghuis, D. O., Geurts Van Kessel, A., Wieringa, B. & Hendriks, W. J. (1995). The mouse gene Ptprf encoding the leukocyte common antigen-related molecule LAR: cloning, characterization, and chromosomal localization. Genomics 27: 124–130.

  31. Simon, D., Knowles, B. B. & Weith, A. (1991). Abnormalities of chromosome 1 and loss of heterozygosity of 1p in primary hepatomas. Oncogene 6: 765–770.

  32. Simon, D. & Carr, B. I. (1995). Integration of hepatitis B virus and alteration of the 1p36 region found in cancerous tissue of primary hepatocellular carcinoma with viral replication evidenced only in noncancerous, cirrhotic tissue. Hepatology 22: 1393–1398.

  33. Tabor, E. (1994). Tumor suppressor genes, growth factor genes, and oncogenes in hepatitis B virus-associated hepatocellular carcinoma. J Med Virol 42: 357–365.

  34. Tahara, E. (1995). Molecular biology of gastric cancer. World J Surg 19: 484–488.

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

  36. Tanaka, K., Hirohata, T., Koga, S., Sugimachi, K., Kanematsu, T., Ohryohji, F., Nawata, H., Ishibashi, H., Maeda, Y., Kiyokawa, H., Tokunaga, K., Irita, Y., Takeshita, S., Arase, Y. & Nishino, N. (1991). Hepatitis C and hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population. Cancer Res 51: 2842–2847.

  37. The Liver Cancer Study Group of Japan (1994). Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. Cancer 74: 2772–2780.

  38. Tokino, T., Fukushige, S., Nakamura, T., Nagaya, T., Murotsu, T., Shiga, K., Aoki, N. & Matsubara, K. (1987). Chromosomal translocation and inverted duplication associated with integrated hepatitis B virus DNA in hepatocellular carcinomas. J Virol 61: 3848–3854.

  39. 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: 6791–6794.

  40. Van Rensburg, S. J., Cook-Mozafarri, P., Van Schlkwyk, D. J., Van Der Watt, J. J., Vincent, T. J. & Purchase, I. F. (1985). Hepatocellular carcinoma and dietary aflatoxin in Mozambique and Transkei. Br J Cancer 51: 713–726.

  41. Wang, J., Chenivesse, X., Henglein, B. & Brechot, C. (1990). Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343: 555–557.

  42. Whelan, S. L., Parkin, D. M. & Masuyer, E. (eds) (1993). Trends in Cancer Incidence and Mortality. IARC Scientific Publ, 102IARC: Lyon

  43. Yeh, S. H., Chen, P. J., Chen, H. L., Lai, M. Y., Wang, C. C. & Chen, D. S. (1994). Frequent genetic alterations at the diastal region of chromosome 1p in human hepatocellular carcinomas. Cancer Res 54: 4188–4192.

  44. Yeh, S. H., Chen, P. J., Lai, M. Y. & Chen, D. S. (1996). Allelic loss on chromosome 4q and 16q in hepatocellular carcinoma: association with elevated α-fetoprotein production. Gastroenterology 110: 184–192.

  45. Zhang, W., Hirohashi, S., Tsuda, H., Shimosato, Y., Yokota, J., Terada, M. & Sugimura, T. (1990). Frequent loss of heterozygosity of chromosomes 16 and 4 in human hepatocellular carcinoma. Jpn J Cancer Res 81: 108–111.

Download references

Author information

Correspondence to J Inazawa.

Rights and permissions

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

Reprints and Permissions

About this article

Cite this article

Sakakura, C., Hagiwara, A., Taniguchi, H. et al. Chromosomal aberrations in human hepatocellular carcinomas associated with hepatitis C virus infection detected by comparative genomic hybridization. Br J Cancer 80, 2034–2039 (1999) doi:10.1038/sj.bjc.6690638

Download citation

Keywords

  • hepatocellular carcinomas
  • CGH
  • chromosomal aberrations

Further reading