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More About: Cell and Molecular Biology of Simian Virus 40: Implications for Human Infections and Disease

Hiroko Ohgaki, Huatao Huang, Matti Haltia, Harri Vainio, Paul Kleihues

Affiliations of authors: H. Ohgaki, H. Huang, H. Vainio, P. Kleihues, International Agency for Research on Cancer, Lyon, France; M. Haltia, Departments of Pathology, Helsinki University Central Hospital and University of Helsinki, Helsinki.

Correspondence to: Hiroko Ohgaki, D.V.M., Ph.D., International Agency for Research on Cancer, Unit of Molecular Pathology, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France.

In a recent review in this Journal, Butel and Lednicky (1) discussed the possible etiologic role of simian virus 40 (SV40) sequences that have been identified in a variety of human neoplasms. In brain tumors, SV40 sequences have been detected at an overall frequency of approximately 35% (1,2,4,5), while surrounding normal brain tissue rarely contained SV40 (4,5). An infectious SV40 wild-type strain has been rescued by transfection of DNA from a choroid plexus carcinoma into permissive monkey kidney cells (2). SV40 is highly oncogenic in hamsters, inducing a variety of tumors including brain tumors. SV40 large T antigen binds to and inactivates several tumor suppressor proteins, including p53 and Rb, and is capable of transforming human cells in vitro (1,2). SV40 was iatrogenically introduced in a large scale into human populations in North America and Europe between 1955 and 1962 through SV40-contaminated polio vaccines (2).

The etiology of brain tumors is still largely unknown. With the exception of therapeutic irradiation, epidemiologic studies have failed to detect unequivocal causative links with environmental or lifestyle factors. Herein, we report on data relevant to the origin of SV40 in brain tumor biopsies and the possible role of SV40 in the evolution of neuroepithelial neoplasms. We have analyzed 13 glioblastomas, 10 ependymomas, and seven choroid plexus papillomas from patients in Finland, a country where SV40-contaminated polio vaccine was not used (3). With the use of a highly specific and sensitive polymerase chain reaction-hybridization method established in our laboratory (4), we failed to detect SV40 sequences in any brain tumor from Finland, whereas 25%-56% of the brain tumors from Switzerland contained SV40 sequences (Table 1, A).Go This corroborates a recent report on the absence of SV40 in mesotheliomas from Finnish patients (3) and strongly suggests that SV40 in human brain tumors originates from SV40-contaminated polio vaccine. This view is further supported by the observation that SV40 sequences were not detected in brain tumors that developed in Swiss patients born before 1923, and who probably did not receive SV40-contaminated polio vaccine. However, SV40 sequences were frequently detected in brain tumors from patients who might have received SV40-contaminated polio vaccine and from patients born after 1963 who were inoculated with SV40-free vaccine (4). Butel and Lednicky (1) reported that approximately 10% of the individuals born after 1962, who had no risk of exposure to contaminated vaccines, had SV40-neutralizing antibody. Thus, these observations indicate that SV40 is able to spread vertically in human populations and is now commonly present even 40 years after SV40-contaminated polio vaccines are no longer used.


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Table 1. Simian virus 40 (SV40) and nervous system tumors

 
Because of the large number of people involved, the etiologic role of SV40 in human cancers needs to be carefully investigated. However, no selective increase in the incidence of brain tumors has been reported in populations that received SV40-contaminated polio vaccine (2), and incidence rates for brain tumors are similar in countries that did (United States and Switzerland) or did not (Finland) use SV40-contaminated vaccine (6) (Table 1,Go B). Thus, the available evidence speaks against a causative role of SV40 in the development of human brain tumors. Instead, its presence probably reflects a bystander infection caused by an intratumoral microenvironment that favors viral replication in humans with latent SV40 infection.

REFERENCES

1 Butel JS, Lednicky JA. Cell and molecular biology of simian virus 40: implications for human infections and disease. J Natl Cancer Inst 1999;91:119-34.[Medline]

2 Carbone M, Rizzo P, Pass HI. Simian virus 40, poliovaccines and human tumors: a review of recent developments. Oncogene 1997;15:1877-88.[Medline]

3 Hirvonen A, Mattson K, Karjalainen A, Ollikainen T, Tammilehto L, Hovi T, et al. Simian virus 40 (SV40)-like DNA sequences not detectable in Finnish mesothelioma patients not exposed to SV40-contaminated polio vaccines. Mol Carcinog 1999;26:93-9.[Medline]

4 Huang H, Reis R, Yonekawa Y, Lopes JM, Kleihues P, Ohgaki H. Identification in human brain tumors of DNA sequences specific for SV40 large T antigen. Brain Pathol 1999;9:33-42.[Medline]

5 Martini F, Iaccheri L, Lazzarin L, Carinci P, Corallini A, Gerosa M, et al. SV40 early region and large T antigen in human brain tumors, peripheral blood cells, and sperm fluids from healthy individuals. Cancer Res 1996;56:4820-5.[Abstract]

6 Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. Cancer incidence in five continents. Vol. VII 1996 (No. 143). Lyon (France): IARC Scientific Publ.; 1997.



             
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