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

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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.

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  • 16 November 2011

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  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.

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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

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  • hepatocellular carcinomas
  • CGH
  • chromosomal aberrations

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