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. 2006 Apr 5;9(1):33–42. doi: 10.1111/j.1750-3639.1999.tb00207.x

Identification in Human Brain Tumors of DNA Sequences Specific for SV40 Large T Antigen

Huatao Huang 1, Rui Reis 1,3, Yasuhiro Yonekawa 2, Jose Manuel Lopes 3, Paul Kleihues 1,4, Hiroko Ohgaki 1,✉
PMCID: PMC8098629  PMID: 9989448

Abstract

Simian virus 40 (SV40) sequences have recently been identified in a variety of human neoplasms, including mesothelioma, osteosarcoma, and brain tumors, but significant discrepancies exist regarding the frequency at which this occurs. The SV40 genome is 70% homologous to JC and BK, two related polyomaviruses that are highly prevalent in humans and which may cause in immune‐compromised patients progressive multifocal leukoencephalopathy (PML) and cystitis, respectively. We have established a specific and sensitive method to identify SV40 sequence in DNA extracted from histological sections, using PCR followed by Southern hybridization to probes specific to the large T region. We found SV40 largeT antigen sequences in all brain tumor types investigated. High frequencies were found in low‐grade astrocytomas, anaplastic astro‐cytomas and secondary glioblastomas derived thereof (13/22, 59%) while somewhat lower frequencies were found in gemistocytic astrocytomas (9/28, 32%) and oligodendrogliomas (3/12, 25%). Primary glioblastomas, giant cell glioblastomas, and gliosarcomas, which clinically develop de novo, contained SV40 sequences in 11–25% of cases. Presence of viral DNA was also observed in pediatric brain tumors, including ependymomas (9/16, 56%), choroid plexus papillomas (6/16, 38%), and medulloblastomas (5/17, 29%). In 8 tumor biopsies with SV40 sequences, the adjacent normal brain tissue was also analyzed but was devoid of viral DNA in all but one case. BK and JC virus sequences were rarely detected, the overall frequencies being 3% and 2%, respectively. It remains to be shown whether the presence of SV40 contributes significantly to malignant transformation or whether certain human neoplasms provide a microenvironment that favors viral replication in humans with latent SV40 infection.

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References

  • 1. Arthur RR, Dagostin S, Shah KV. (1989) Detection of BK virus and JC virus in urine and brain tissue by the polymerase chain reaction. J Clin Microbiol 27: 1174–1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Arthur RR, Grossman SA, Ronnett BM, Bigner SH, Vogel‐stein B, Shah KV. (1994) Lack of association of human polyomaviruses with human brain tumors. J Neurooncol 20: 55–58. [DOI] [PubMed] [Google Scholar]
  • 3. Barbanti Brodano G, Martini F, De Mattei M, Lazzarin L, Corallini A, Tognon M. (1998) BK and JC human polyomaviruses and Simian virus 40: natural history of infection in humans, experimental oncogenicity, and association with human tumors. Adv Virus Res 50: 69–99. [DOI] [PubMed] [Google Scholar]
  • 4. Bergsagel DJ, Finegold MJ, Butel JS, Kupsky WJ, Garcea RL. (1992) DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood. N Engl J Med 326: 988–993. [DOI] [PubMed] [Google Scholar]
  • 5. Butel JS, Lednicky JA, Stewart AR, Garcea RL, Finegold MJ. (1997) SV40 and human brain tumors. J Neurovirol 3 Suppl 1: S78–S79. [PubMed] [Google Scholar]
  • 6. Carbone M, Pass HI, Rizzo P, Marinetti M, Di Muzio M, Mew DJ, Levine AS, Procopio A. (1994) Simian virus 40‐like DNA sequences in human pleural mesothelioma. Oncogene 9: 1781–1790. [PubMed] [Google Scholar]
  • 7. Carbone M, Rizzo P, Grimley PM, Procopio A, Mew DJ, Shridhar V, De Bartolomeis A, Esposito V, Giuliano MT, Steinberg SM, Levine AS, Giordano A, Pass HI. (1997) Simian virus‐40 large‐T antigen binds p53 in human mesotheliomas. Nat Med 3: 908–912. [DOI] [PubMed] [Google Scholar]
  • 8. Carbone M, Rizzo P, Pass HI. (1997) Simian virus 40, poliovaccines and human tumors: a review of recent developments. Oncogene 15: 1877–1888. [DOI] [PubMed] [Google Scholar]
  • 9. Carbone M, Rizzo P, Procopio A, Giuliano M, Pass HI, Gebhardt MC, Mangham C, Hansen M, Malkin DF, Bushart G, Pompetti F, Picci P, Levine AS, Bergsagel JD, Garcea RL. (1996) SV40‐like sequences in human bone tumors. Oncogene 13: 527–535. [PubMed] [Google Scholar]
  • 10. Chauvin C, Suh M, Remy C, Benabid AL. (1990) Failure to detect viral genomic sequences of three viruses (herpes simplex, simian virus 40 and adenovirus) in human and rat brain tumors. Ital J Neurol Sci 11: 347–357. [DOI] [PubMed] [Google Scholar]
  • 11. De Mattei M, Martini F, Corallini A, Gerosa M, Scotlandi K, Carinci P, Barbanti BG, Tognon M. (1995) High incidence of BK virus large‐T‐antigen‐coding sequences in normal human tissues and tumors of different histotypes. Int J Cancer 61: 756–760. [DOI] [PubMed] [Google Scholar]
  • 12. De Villers EM. (1997) SV40: A possible human poly‐omavirus workshop. National Institutes of Health, Bethesda, MD, 27–28 Jan 1997 Transcripts SAG Corp Washington DC 20008 Vol. 1: 176–180. [Google Scholar]
  • 13. Dorries K, Loeber G, Meixensberger J. (1987) Association of polyomaviruses JC, SV40, and BK with human brain tumors. Virology 160: 268–270. [DOI] [PubMed] [Google Scholar]
  • 14. Dorries K, Vogel E, Gunther S, Czub S. (1994) Infection of human polyomaviruses JC and BK in peripheral blood leukocytes from immunocompetent individuals. Virology 198: 59–70. [DOI] [PubMed] [Google Scholar]
  • 15. Eibl RH, Kleihues P, Jat PS, Wiestler OD. (1994) A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen. Am J Pathol 144: 556–564. [PMC free article] [PubMed] [Google Scholar]
  • 16. Fanning E, Knippers R. (1992) Structure and function of simian virus 40 large tumor antigen. Annu Rev Biochem 61: 55–85. [DOI] [PubMed] [Google Scholar]
  • 17. Galateau‐Salle F, Bidet PH, Iwatsubo Y, Gennetay E, Renier A, Letourneux M, Pairon JC, Moritz S, Brochard P, Jaurand MC, Freymuth F. (1998) SV40‐like sequences in pleural mesothelioma, bronchopulmonary carcinoma, and non‐malignant pulmonary diseases. J Pathol 184: 252–257. [DOI] [PubMed] [Google Scholar]
  • 18. Gardner S. (1973) Prevalence in England of antibody to human polyoma virus(BK). BMJ 1: 77–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Geissler E. (1990) SV40 and human brain tumors. Prog Med Virol 37: 211–222. [PubMed] [Google Scholar]
  • 20. Greenlee JE, Becker LE, Narayan O, Johnson RT. (1978) Failure to demonstrate papovavirus tumor antigen in human cerebral neoplasms. Ann Neurol 3: 479–481. [DOI] [PubMed] [Google Scholar]
  • 21. Kleihues P, Wiestler OD, Ohgaki H, Aguzzi A. (1998) Animal models of tumors of the nervous system. In: The Gliomas, Berger M, Wilson C, (Eds), pp. 124–133, WB. Saunders: Philadelphia . [Google Scholar]
  • 22. Kosaka H, Sano Y, Matsukado Y, Sairenji T, Hinuma Y (1980) Failure to detect papovavirus‐associated T antigens in human brain tumor cells by anticomplement immunofluorescence. J Neurosurg 52: 367–370. [DOI] [PubMed] [Google Scholar]
  • 23. Krainer M, Schenk T, Zielinski CC, Muller C. (1995) Failure to confirm presence of SV40 sequences in human tumours (letter). Eur J Cancer 31A: 1893. [DOI] [PubMed] [Google Scholar]
  • 24. Krieg P, Amtmann E, Jonas D, Fischer H, Zang K, Sauer G. (1981) Episomal simian virus 40 genomes in human brain tumors. Proc Natl Acad Sci USA 78: 6446–6450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Krieg P, Scherer G. (1984) Cloning of SV40 genomes from human brain tumors. Virology 138: 336–340. [DOI] [PubMed] [Google Scholar]
  • 26. Krynska B, Otte J, Franks R, Khalili K, Croul S. (1998) Human ubiquitous JCV.CV T‐antigen gene induces brain tumors in experimental animals. Oncogene (in press). [DOI] [PubMed] [Google Scholar]
  • 27. Lantos PL, VandenBerg SR, Kleihues P. (1996) Tumours of the Nervous System. In: Greenfield's Neuropathology, Graham DI, Lantos PL, (Eds), 9, 6th Edition, pp. 583–879, Arnold: London . [Google Scholar]
  • 28. Lednicky JA, Butel JS. (1997) A coupled PCR and restriction digest method for the detection and analysis of the SV40 regulatory region in infected‐cell lysates and clinical samples. J Virol Methods 64: 1–9. [DOI] [PubMed] [Google Scholar]
  • 29. Lednicky JA, Garcea RL, Bergsagel DJ, Butel JS. (1995) Natural simian virus 40 strains are present in human choroid plexus and ependymoma tumors. Virology 212: 710–717. [DOI] [PubMed] [Google Scholar]
  • 30. Lednicky JA, Stewart AR, Jenkins JJ, Finegold MJ, Butel JS. (1997) SV40 DNA in human osteosarcomas shows sequence variation among T‐antigen genes. Int J Cancer 72: 791–800. [DOI] [PubMed] [Google Scholar]
  • 31. Lozano G, Levine AJ. (1991) Tissue‐specific expression of p53 in transgenic mice is regulated by intron sequences. Mol Carcinog 4: 3–9. [DOI] [PubMed] [Google Scholar]
  • 32. Martini F, Laccheri L, Lazzarin L, Carinci P, Corallini A, Gerosa M, Luzzolino P, Barbanti Brodano G, Tognon M. (1996) SV40 early region and large T antigen in human brain tumors, peripheral blood cells, and sperm fluids from healthy individuals. Cancer Res 56: 4820–4825. [PubMed] [Google Scholar]
  • 33. Meinke W, Goldstein DA, Smith RA. (1979) Simian virus 40‐related DNA sequences in a human brain tumor. Neurology 29: 1590–1594. [DOI] [PubMed] [Google Scholar]
  • 34. Melnick JL, Stinebaugh S. (1962) Excretion of vacuolating SV‐40 virus (Papova Virus Group) after ingestion as a contaminant of oral poliovaccine. Proc Soc Exp Biol Med 109: 965–968. [DOI] [PubMed] [Google Scholar]
  • 35. Monini P, De Lellis L, Barnanti‐Brodano G. (1995) Association of BK and JC human polyomaviruses and SV40 with human tumors. In: DNA Tumor Viruses. Oncogenic Mechanisms, Barnanti‐Brodano G, Bendinelli M, Friedman H, (Eds), pp. 51–73, Plenum Press: New York . [Google Scholar]
  • 36. Morris JA, Johnson KM, Aulisio CG, Chanock RM, Knight V (1961) Clinical and serologic responses in volunteers given vacuolating virus (SV40) by respiratory route. Proc Soc Exp Biol Med 108: 56–59. [DOI] [PubMed] [Google Scholar]
  • 37. Ohsumi S, Ikehara I, Motoi M, Ogawa K, Nagashima K, Yasui K. (1985) Induction of undifferentiated brain tumors in rats by a human polyomavirus (JC virus). Jpn J Cancer Res 76: 429–431. [PubMed] [Google Scholar]
  • 38. Pacini F, Vivaldi A, Santoro M, Fedele M, Fusco A, Romei C, Basolo F, Pinchera A. (1998) Simian virus 40‐like DNA sequences in human papillary thyroid carcinomas. Oncogene 16: 665–669. [DOI] [PubMed] [Google Scholar]
  • 39. Palmiter RD, Chen HY, Messing A, Brinster RL. (1985) SV40 enhancer and large‐T antigen are instrumental in development of choroid plexus tumours in transgenic mice. Nature 316: 457–460. [DOI] [PubMed] [Google Scholar]
  • 40. Pepper C, Jasani B, Navabi H, Wynford TD, Gibbs AR. (1996) Simian virus 40 large T antigen (SV40LTAg) primer specific DNA amplification in human pleural mesothelioma tissue. Thorax 51: 1074–1076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Peraud A, Watanabe K, Plate KH, Yonekawa Y, Kleihues P, Ohgaki H. (1997) p53 Mutations versus EGF receptor expression in giant cell glioblastomas. J Neuropath Exp Neurol 56: 1235–1241. [DOI] [PubMed] [Google Scholar]
  • 42. Porcu P, Ferber A, Pietrzkowski Z, Roberts CT, Adamo M, LeRoith D, Baserga R. (1992) The growth‐stimulatory effect of simian virus 40 T antigen requires the interaction of insulinlike growth factor 1 with its receptor. Mol Cell Biol 12: 5069–5077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Ray FA, Peabody DS, Cooper JL, Cram LS, Kraemer PM. (1990) SV40 T antigen alone drives karyotype instability that precedes neopiastic transformation of human dipioid fibroblasts. J Cell Biochem 42: 13–31. [DOI] [PubMed] [Google Scholar]
  • 44. Ressetar HG, Prakash O, Frisque RJ, Webster HD, Re RN, Stoner GL. (1993) Expression of viral T‐antigen in pathological tissues from transgenic mice carrying JC‐SV40 chimeric DNAs. Mol Chem Neuropathol 20: 59–79. [DOI] [PubMed] [Google Scholar]
  • 45. Scherneck S, Rudolph M, Geissler E, Vogel F, Lubbe L, Wahlte H, Nisch G, Weickmann F, Zimmermann W. (1979) Isolation of a SV40‐like Papovavirus from a human glioblastoma. Int J Cancer 24: 523–531. [DOI] [PubMed] [Google Scholar]
  • 46. Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. (1993) Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin‐like growth factor receptor. Proc Natl Acad Sci USA 90: 11217–11221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Shah K, Nathanson N. (1976) Human exposure to SV40: review and comment. Am J Epidemiol 103: 1–12. [DOI] [PubMed] [Google Scholar]
  • 48. Shah KV, Daniel RW, Strickler HD, Goedert JJ. (1997) Investigation of human urine for genomic sequences of the primate polyomaviruses simian virus 40, BK virus, and JC virus. J Infect Dis 176: 1618–1621. [DOI] [PubMed] [Google Scholar]
  • 49. Soriano F, Shelburne CE, Gokcen M. (1974) Simian virus 40 in a human cancer. Nature 249: 421–424. [DOI] [PubMed] [Google Scholar]
  • 50. Stewart AR, Lednicky JA, Butel JS. (1998) Sequence analyses of human tumor‐associated SV40 DNAs and SV40 viral isolates from monkeys and humans. J Neurovirol 4: 182–193. [DOI] [PubMed] [Google Scholar]
  • 51. Stewart N, Bacchetti S. (1991) Expression of SV40 large T antigen, but not small t antigen, is required for the induction of chromosomal aberrations in transformed human cells. Virology 180: 49–57. [DOI] [PubMed] [Google Scholar]
  • 52. Stoian M, Suru M, Hozoc M, Losipenco M, Athanasiu P, Nastac E, Arseni C, Alexianu D. (1984) Investigations on the presence of papova virus in certain forms of human cancer. Note 2. Brain tumors. Virologie 35: 127–132. [PubMed] [Google Scholar]
  • 53. Strickler HD, Goedert JJ, Fleming M, Travis WD, Williams AE, Rabkin CS, Daniel RW, Shah KV. (1996) Simian virus 40 and pleural mesothelioma in humans. Cancer Epidemiol Biomarkers Prev 5: 473–475. [PubMed] [Google Scholar]
  • 54. Suzuki SO, Mizoguchi M, Iwaki T. (1997) Detection of SV40 T antigen genome in human gliomas. Brain Tumor Pathol 14: 125–129. [DOI] [PubMed] [Google Scholar]
  • 55. Tabuchi K, Kirsch WM, Low M, Gaskin D, Van BJ, Maa S. (1978) Screening of human brain tumors for SV40‐related T antigen. Int J Cancer 21: 12–17. [DOI] [PubMed] [Google Scholar]
  • 56. Tognon M, Casalone R, Martini F, De Mattei M, Granata P, Minelli E, Arcuri C, Collini P, Bocchini V. (1996) Large T antigen coding sequences of two DNA tumor viruses, BK and SV40, and nonrandom chromosome changes in two glioblastoma cell lines. Cancer Genet Cytogenet 90: 17–23. [DOI] [PubMed] [Google Scholar]
  • 57. Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H. (1998) PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropath Exp Neurol 57: 684–689. [DOI] [PubMed] [Google Scholar]
  • 58. Volter C, zur Hausen H, Alber D, De Villiers E. (1997) Screening human tumor samples with a broad‐spectrum polymerase chain reaction method for the detection of polyomaviruses. Virology 237: 389–396. [DOI] [PubMed] [Google Scholar]
  • 59. Walker DL, Padgett BL, ZuRhein GM, Albert AE, Marsh RF. (1973) Human papovavirus (JC): Induction of brain tumors in hamsters. Science 181: 674–676. [DOI] [PubMed] [Google Scholar]
  • 60. Walsh JW, Zimmer SG, Perdue ML. (1982) Role of viruses in the induction of primary intracranial tumors. Neurosurgery 10: 643–662. [DOI] [PubMed] [Google Scholar]
  • 61. Watanabe K, Peraud A, Gratas C, Wakai S, Kleihues P, Ohgaki H. (1998) p53 and PTEN gene mutations in gemistocytic astrocytomas. Acta Neuropath 95: 559–564. [DOI] [PubMed] [Google Scholar]
  • 62. Watanabe K, Tachibana O, Sato K, Yonekawa Y, Kleihues P, Ohgaki H. (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6: 217–224. [DOI] [PubMed] [Google Scholar]
  • 63. Weiss AF, Portmann R, Fischer H, Simon J, Zang KD. (1975) Simian virus 40‐related antigens in three human meningiomas with defined chromosome loss. Proc Natl Acad Sci USA 72: 609–613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. White FA, Ishaq M, Stoner GL, Frisque RJ. (1992) JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy. J Virol 66: 5726–5734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Wold WS, Mackey JK, Brackmann KH, Takemori N, Rigden P, Green M. (1978) Analysis of human tumors and human malignant cell lines for BK virus‐specific DNA sequences. Proc Natl Acad Sci USA 75: 454–458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Zimmermann W, Schernick S, Geissler E, Nisch G. (1981) Demonstration of SV40‐related tumour antigen in human meningiomas by different hamster SV40‐T‐antisera. Acta Virol 25: 199–204. [PubMed] [Google Scholar]

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