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Viral integration, fragile sites, and proto-oncogenes in human neoplasia

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Summary

To evaluate the trend of viral integration in the human genome, chromosomal localization of five DNA-containing viruses compiled from literature data was compared to the location of fragile sites and protooncogenes. A total of 35 regionally mapped viral integration sites from tumors and transformed cells were distributed over 19 chromosomes. Of the 35 integration sites 23 (66%) were at the bands of fragile sites, and 7 were one band away (20%). This statistically defines the correlation as highly significant (P = 0.0000183, Fisher's F-test). Five integration sites did not correspond to the location of a fragile site. Thirteen integration sites and proto-oncogenes mapped at the same bands (37%), 6. (17%) were one band apart, and at 16 integration sites (46%) no proto-oncogenes were localized (P = 0.00491). Eighteen viral integration sites, fragile sites, and protooncogenes (51%) were localized at the same bands or one band distant. This clustering of viral integration sites, fragile sites, and proto-oncogenes is statistically highly significant (P = 0.0000118), and indicates nonrandom viral integration in the human genome.

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References

  • Alhadeff B, Purrello M, Romani M, Szabo P, Gluzman T, Siniscalco M (1987) The adenovirus 12 modification site 1p(A1ZMZ) is also a site of preferential viral integration in human cells transfected with the hybrid recombinant virus adenovirus 5/ SV40 (abstract). (9th International Workshop on Human Gene Mapping) Cytogenet Cell Genet 46:569

    Google Scholar 

  • Ambros PF, Karlic HI (1987) Chromosomal insertion of human papillomavirus 18 sequences in HeLa cells detected by non-isotopic in situ hybridization and reflection contrast microscopy. Hum Genet 77:251–254

    Google Scholar 

  • Bishop JM (1987) The molecular genetics of cancer. Science 235:305–311

    Google Scholar 

  • Bowcock AM, Pinto MR, Bey E, Kuyl JM, Dusheiko GM, Bernstein R (1985) The PLC/PRF/5 human hepatoma cell line. II. Chromosomal assignment of hepatitis B virus integration sites. Cancer Genet Cytogenet 18:19–26

    Google Scholar 

  • Cannizzaro LA, Durst M, Mendez MJ, Hecht BK, Hecht F (1988) Regional chromosome localization of human papillomavirus integration sites near fragile sites, oncogenes and cancer chromosome breakpoints. Cancer Genet Cytogenet 33:93–98

    Google Scholar 

  • Croce C (1981) Integration of oncogenic viruses in mammalian cells. Int Rev Cytol 71:1–17

    Google Scholar 

  • Dejean AL, Bougueleret L, Grzeschik KM, Tiollais P (1986) Hepatitis B virus DNA integration in a sequence homologous to v-erbA and steroid receptor genes in a hepatocellular carcinoma. Nature 322:70–72

    Google Scholar 

  • Durnam DM, Menninger JC, Chandler SH, Smith PP, McDougall J (1988) A fragile site in the human U2 small nuclear RNA gene cluster is revealed by adenovirus type 12 infection. Mol Cell Biol 8:1853–1867

    Google Scholar 

  • Durst M, Croce CM, Gissmann L, Schwarz E, Huebner K (1987) Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas. Proc Natl Acad Sci USA 84:1070–1074

    Google Scholar 

  • Hecht F (1988a) Fragile sites, cancer chromosome breakpoints and oncogenes all cluster in light G-bands. Cancer Genet Cytogenet 31:17–24

    Google Scholar 

  • Hecht F (1988b) Fragile site update (Appendix A). Cancer Genet Cytogenet 31:125–128

    Google Scholar 

  • Henderson A (1983) Localization of viral-specific DNA in the mammalian chromosome complement by cytological hybridization. In: Rowley J, Ultman J (eds) Chromosomes and cancer: from molecules to man. Academic Press, New York London, pp 247–272

    Google Scholar 

  • Henderson A, Ripley S, Heller M, Kieff E (1983) Human chromosome association of Epstein-Barr virus DNA in a Burkitt tumor cell line and in lymphocytes growth-transformed in vitro. Proc Natl Acad Sci USA 80:1987–1991

    Google Scholar 

  • Henderson A, Ripley S, Hino O, Rogler CE (1988) Identification of a chromosomal aberration associated with a hepatitis B DNA integration site in human cells. Cancer Genet Cytogenet 30:269–275

    Google Scholar 

  • Hino O, Shows T, Rogler C (1986) Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17:18 translocation. Proc Natl Acad Sci USA 83:8338–8342

    Google Scholar 

  • Human Gene Mapping 9 (1987) 9th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 46:1–762

    Google Scholar 

  • Human Gene Mapping 9.5 (1989) Update to the 9th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 49:1–258

    Google Scholar 

  • Lazo P, DiPaolo JA, Popescu NC (1989) Amplification of viral transforming genes of human papillomavirus-18 and its 5′ flanking sequences located near myc proto-oncogene in HeLa cells. Cancer Res 49:4305–4310

    Google Scholar 

  • LeBeau MM (1988) Chromosomal fragile sites and cancer-specific breakpoints — a moderating viewpoint. Cancer Genet Cytogenet 31:55–61

    Google Scholar 

  • Minceva A, Gissmann L, Hausen H zur (1987) Chromosomal integration sites of human papillomaviruses DNA in three cervical cancer cell lines mapped by in situ hybridization. Med Microbiol Immunol 176:245–256

    Google Scholar 

  • Mitelman F (1988) Catalog of chromosome aberrations in cancer. Liss, New York

    Google Scholar 

  • Mitelman F, Heim S (1988) Consistent involvement of only 71 of the 329 chromosomal bands of the human genome in primary neoplasia-associated rearrangements. Cancer Res 48:7115–7119

    Google Scholar 

  • Nagaya T, Nakamura T, Tokino T, Tsurimoto T, Imai M, Mayumi T, Kamino K, Yamamura K, Matsubara K (1987) The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma. Genes Dev 1:773–782

    Google Scholar 

  • Pfister H (1987) Human papillomaviruses and genital cancer. Adv Cancer Res 48:113–147

    Google Scholar 

  • Popescu NC, DiPaolo JA, Amsbaugh SC (1987a) Integration sites of human papillomavirus 18 DNA sequences on HeLa cell chromosomes. Cytogenet Cell Genet 44:58–62

    Google Scholar 

  • Popescu NC, Amsbaugh SC, DiPaolo JA (1987b) Human papillomavirus type 18 DNA is integrated at a single chromosome site in cervical carcinoma cell line SW756. J Virol 51:1682–1685

    Google Scholar 

  • Rabin M, Uhlenbeck OC, Steffensen DM, Mangel WF (1984) Chromosomal sites of integration of Simian virus 40 DNA sequences mapped by in situ hybridization in two transformed hybrid cell lines. J Virol 49:445–451

    Google Scholar 

  • Robinson HL, Gagnon G (1986) Patterns of proviral insertion and deletion in avian leukosis virus-induced lymphomas. J Virol 57:28–36

    Google Scholar 

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

    Google Scholar 

  • Rohdewohld H, Weiher H, Reik W, Jaenisch R, Breindl M (1987) Retrovirus integration and chromatin structure: Moloney murine leukemia proviral integration sites map near DNaselhypersensitive sites. J Virol 61:336–343

    Google Scholar 

  • Sandberg AA (1980) Chromosomes in human cancer and leukemia. Elsevier/North-Holland, New York Amsterdam

    Google Scholar 

  • Shaul Y, Garcia PD, Schonberg S, Rutter WJ (1986) Integration of hepatitis B virus DNA in chromosome-specific satellite sequences. J Virol 59:731–734

    Google Scholar 

  • Shiraishi Y, Taguchi T, Ohta Y, Hirai K (1985) Chromosomal localization of the Epstein-Barr virus (EBV) genome in Bloom's syndrome B-lymphoblastoid cell lines transformed with EBV. Chromosoma 93:157–164

    Google Scholar 

  • Sutherland GR, Simmers RN (1988) No statistical association between common fragile sites and nonrandom chromosome breakpoints in cancer cells. Cancer Genet Cytogenet 31:9–15

    Google Scholar 

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

    Google Scholar 

  • Trescol-Biemont MC, Biemont C, Daillie J (1987) Localization polymorphism of EBV DNA genomes in the chromosomes of Burkitt lymphoma cell lines. Chromosoma 95:144–147

    Google Scholar 

  • Vijaya S, Steffen D, Robinson HL (1986) Acceptor sites for retroviral integrations map near DNaseI-hypersensitive sites in chromatin. J Virol 60:683–692

    Google Scholar 

  • Wang HP, Rogler CE (1988) Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas. Cytogenet Cell Genet 48:72–78

    Google Scholar 

  • Weinberg RA (1980) Integrated genomes of animal viruses. Annu Rev Biochem 49:197–226

    Google Scholar 

  • Yunis JJ, Soreng AL, Bowe AE (1987) Fragile sites are targets of diverse mutagens and carcinogens. Oncogene 1:59–69

    Google Scholar 

  • Zhou YZ, Slagle BL, Donehower LA, Vantuinen P, Ledbetter DH, Butel JS (1988) Structural analysis of a hepatitis B virus genome integrated into chromosome 17p of a human hepatocellular carcinoma. J Virol 62:4224–4231

    Google Scholar 

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Authors and Affiliations

  1. Laboratory of Biology, Division of Cancer Etiology, National Cancer Institute, Bldg. 37 — Room 2A19, 20892, Bethesda, MD, USA

    Nicholas C. Popescu & Joseph A. DiPaolo

  2. Department of Biology, Faculty of Veterinary Medicine, University of Belgrade, Belgrade, Yugoslavia

    Drazen Zimonjic

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  1. Nicholas C. Popescu
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  2. Drazen Zimonjic
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  3. Joseph A. DiPaolo
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Popescu, N.C., Zimonjic, D. & DiPaolo, J.A. Viral integration, fragile sites, and proto-oncogenes in human neoplasia. Hum Genet 84, 383–386 (1990). https://doi.org/10.1007/BF00195804

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  • DOI: https://doi.org/10.1007/BF00195804

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