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. 1996 Oct;70(10):7280–7284. doi: 10.1128/jvi.70.10.7280-7284.1996

A t(3;8) chromosomal translocation associated with hepatitis B virus intergration involves the carboxypeptidase N locus.

P Pineau 1, A Marchio 1, B Terris 1, M G Mattei 1, Z X Tu 1, P Tiollais 1, A Dejean 1
PMCID: PMC190789  PMID: 8794383

Abstract

Integrated hepatitis B virus (HBV) DNA is found in the great majority of human hepatocellular carcinomas, suggesting that these viral integrations may be implicated in liver oncogenesis. Besides the insertional mutagenesis characterized in a few selected cases and the contribution of viral transactivators to cell transformation to malignancy, HBV has been shown to generate gross chromosomal rearrangements potentially involved in carcinogenesis. Here, we report a t(3;8) chromosomal translocation present in a hepatocellular carcinoma developed in noncirrhotic liver tissue. One side of the translocation, in 8p23, is shown to be in the vicinity of the carboxypeptidase N gene, a locus that is heavily transcribed in liver tissue and frequently deleted in hepatocellular carcinomas and other epithelial tumors. The other side of the translocation, in 3q27-29, is widely implicated in several types of translocations occurring in different malignancies, such as large-cell lymphomas. The present data strongly support a model in which HBV-induced chromosomal rearrangements play a key role during multistep liver oncogenesis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams M. D., Kelley J. M., Gocayne J. D., Dubnick M., Polymeropoulos M. H., Xiao H., Merril C. R., Wu A., Olde B., Moreno R. F. Complementary DNA sequencing: expressed sequence tags and human genome project. Science. 1991 Jun 21;252(5013):1651–1656. doi: 10.1126/science.2047873. [DOI] [PubMed] [Google Scholar]
  2. Biegel J. A., Nycum L. M., Valentine V., Barr F. G., Shapiro D. N. Detection of the t(2;13)(q35;q14) and PAX3-FKHR fusion in alveolar rhabdomyosarcoma by fluorescence in situ hybridization. Genes Chromosomes Cancer. 1995 Mar;12(3):186–192. doi: 10.1002/gcc.2870120305. [DOI] [PubMed] [Google Scholar]
  3. Buendia M. A. Hepatitis B viruses and hepatocellular carcinoma. Adv Cancer Res. 1992;59:167–226. doi: 10.1016/s0065-230x(08)60306-1. [DOI] [PubMed] [Google Scholar]
  4. Cohen A. J., Li F. P., Berg S., Marchetto D. J., Tsai S., Jacobs S. C., Brown R. S. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med. 1979 Sep 13;301(11):592–595. doi: 10.1056/NEJM197909133011107. [DOI] [PubMed] [Google Scholar]
  5. Crozat A., Aman P., Mandahl N., Ron D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 1993 Jun 17;363(6430):640–644. doi: 10.1038/363640a0. [DOI] [PubMed] [Google Scholar]
  6. Dejean A., Bougueleret L., Grzeschik K. H., Tiollais P. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature. 1986 Jul 3;322(6074):70–72. doi: 10.1038/322070a0. [DOI] [PubMed] [Google Scholar]
  7. Dejean A., Sonigo P., Wain-Hobson S., Tiollais P. Specific hepatitis B virus integration in hepatocellular carcinoma DNA through a viral 11-base-pair direct repeat. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5350–5354. doi: 10.1073/pnas.81.17.5350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Delattre O., Zucman J., Plougastel B., Desmaze C., Melot T., Peter M., Kovar H., Joubert I., de Jong P., Rouleau G. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992 Sep 10;359(6391):162–165. doi: 10.1038/359162a0. [DOI] [PubMed] [Google Scholar]
  9. Deweindt C., Kerckaert J. P., Tilly H., Quief S., Nguyen V. C., Bastard C. Cloning of a breakpoint cluster region at band 3q27 involved in human non-Hodgkin's lymphoma. Genes Chromosomes Cancer. 1993 Nov;8(3):149–154. doi: 10.1002/gcc.2870080303. [DOI] [PubMed] [Google Scholar]
  10. Emi M., Fujiwara Y., Nakajima T., Tsuchiya E., Tsuda H., Hirohashi S., Maeda Y., Tsuruta K., Miyaki M., Nakamura Y. Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer, and lung cancer. Cancer Res. 1992 Oct 1;52(19):5368–5372. [PubMed] [Google Scholar]
  11. Fritsch E. F., Lawn R. M., Maniatis T. Molecular cloning and characterization of the human beta-like globin gene cluster. Cell. 1980 Apr;19(4):959–972. doi: 10.1016/0092-8674(80)90087-2. [DOI] [PubMed] [Google Scholar]
  12. Fujiwara Y., Emi M., Ohata H., Kato Y., Nakajima T., Mori T., Nakamura Y. Evidence for the presence of two tumor suppressor genes on chromosome 8p for colorectal carcinoma. Cancer Res. 1993 Mar 1;53(5):1172–1174. [PubMed] [Google Scholar]
  13. Hickman D., Risch A., Buckle V., Spurr N. K., Jeremiah S. J., McCarthy A., Sim E. Chromosomal localization of human genes for arylamine N-acetyltransferase. Biochem J. 1994 Feb 1;297(Pt 3):441–445. doi: 10.1042/bj2970441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kerckaert J. P., Deweindt C., Tilly H., Quief S., Lecocq G., Bastard C. LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nat Genet. 1993 Sep;5(1):66–70. doi: 10.1038/ng0993-66. [DOI] [PubMed] [Google Scholar]
  15. Mandahl N., Höglund M., Mertens F., Rydholm A., Willén H., Brosjö O., Mitelman F. Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors. Genes Chromosomes Cancer. 1994 Mar;9(3):207–215. doi: 10.1002/gcc.2870090309. [DOI] [PubMed] [Google Scholar]
  16. Matsubara K., Tokino T. Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis. Mol Biol Med. 1990 Jun;7(3):243–260. [PubMed] [Google Scholar]
  17. Mattei M. G., Philip N., Passage E., Moisan J. P., Mandel J. L., Mattei J. F. DNA probe localization at 18p113 band by in situ hybridization and identification of a small supernumerary chromosome. Hum Genet. 1985;69(3):268–271. doi: 10.1007/BF00293038. [DOI] [PubMed] [Google Scholar]
  18. Meyer M., Wiedorn K. H., Hofschneider P. H., Koshy R., Caselmann W. H. A chromosome 17:7 translocation is associated with a hepatitis B virus DNA integration in human hepatocellular carcinoma DNA. Hepatology. 1992 Apr;15(4):665–671. doi: 10.1002/hep.1840150419. [DOI] [PubMed] [Google Scholar]
  19. Mount S. M. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. doi: 10.1093/nar/10.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Popper H., Shafritz D. A., Hoofnagle J. H. Relation of the hepatitis B virus carrier state to hepatocellular carcinoma. Hepatology. 1987 Jul-Aug;7(4):764–772. doi: 10.1002/hep.1840070425. [DOI] [PubMed] [Google Scholar]
  21. Rabbitts T. H. Chromosomal translocations in human cancer. Nature. 1994 Nov 10;372(6502):143–149. doi: 10.1038/372143a0. [DOI] [PubMed] [Google Scholar]
  22. Rodriguez E., Sreekantaiah C., Chaganti R. S. Genetic changes in epithelial solid neoplasia. Cancer Res. 1994 Jul 1;54(13):3398–3406. [PubMed] [Google Scholar]
  23. Schröder C. H., Zentgraf H. Hepatitis B virus related hepatocellular carcinoma: chronicity of infection--the opening to different pathways of malignant transformation? Biochim Biophys Acta. 1990 Dec 11;1032(2-3):137–156. doi: 10.1016/0304-419x(90)90001-h. [DOI] [PubMed] [Google Scholar]
  24. Smith C. A., Smith G., Wolf C. R. Genetic polymorphisms in xenobiotic metabolism. Eur J Cancer. 1994;30A(13):1921–1935. doi: 10.1016/0959-8049(94)00382-f. [DOI] [PubMed] [Google Scholar]
  25. Sreekantaiah C., Leong S. P., Karakousis C. P., McGee D. L., Rappaport W. D., Villar H. V., Neal D., Fleming S., Wankel A., Herrington P. N. Cytogenetic profile of 109 lipomas. Cancer Res. 1991 Jan 1;51(1):422–433. [PubMed] [Google Scholar]
  26. Steel D. M., Whitehead A. S. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today. 1994 Feb;15(2):81–88. doi: 10.1016/0167-5699(94)90138-4. [DOI] [PubMed] [Google Scholar]
  27. Takada S., Gotoh Y., Hayashi S., Yoshida M., Koike K. Structural rearrangement of integrated hepatitis B virus DNA as well as cellular flanking DNA is present in chronically infected hepatic tissues. J Virol. 1990 Feb;64(2):822–828. doi: 10.1128/jvi.64.2.822-828.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tiollais P., Pourcel C., Dejean A. The hepatitis B virus. Nature. 1985 Oct 10;317(6037):489–495. doi: 10.1038/317489a0. [DOI] [PubMed] [Google Scholar]
  29. Tokino T., Fukushige S., Nakamura T., Nagaya T., Murotsu T., Shiga K., Aoki N., Matsubara K. Chromosomal translocation and inverted duplication associated with integrated hepatitis B virus in hepatocellular carcinomas. J Virol. 1987 Dec;61(12):3848–3854. doi: 10.1128/jvi.61.12.3848-3854.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tokino T., Tamura H., Hori N., Matsubara K. Chromosome deletions associated with hepatitis B virus integration. Virology. 1991 Dec;185(2):879–882. doi: 10.1016/0042-6822(91)90564-r. [DOI] [PubMed] [Google Scholar]
  31. Valenzuela P., Gray P., Quiroga M., Zaldivar J., Goodman H. M., Rutter W. J. Nucleotide sequence of the gene coding for the major protein of hepatitis B virus surface antigen. Nature. 1979 Aug 30;280(5725):815–819. doi: 10.1038/280815a0. [DOI] [PubMed] [Google Scholar]
  32. Wang J., Chenivesse X., Henglein B., Bréchot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990 Feb 8;343(6258):555–557. doi: 10.1038/343555a0. [DOI] [PubMed] [Google Scholar]
  33. Yaremko M. L., Wasylyshyn M. L., Paulus K. L., Michelassi F., Westbrook C. A. Deletion mapping reveals two regions of chromosome 8 allele loss in colorectal carcinomas. Genes Chromosomes Cancer. 1994 May;10(1):1–6. doi: 10.1002/gcc.2870100102. [DOI] [PubMed] [Google Scholar]
  34. Ye B. H., Lista F., Lo Coco F., Knowles D. M., Offit K., Chaganti R. S., Dalla-Favera R. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science. 1993 Oct 29;262(5134):747–750. doi: 10.1126/science.8235596. [DOI] [PubMed] [Google Scholar]
  35. Zhou Y. Z., Slagle B. L., Donehower L. A., vanTuinen P., Ledbetter D. H., Butel J. S. Structural analysis of a hepatitis B virus genome integrated into chromosome 17p of a human hepatocellular carcinoma. J Virol. 1988 Nov;62(11):4224–4231. doi: 10.1128/jvi.62.11.4224-4231.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

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