SV40 infection in human cancers
Authors: P. Brousset, J. Sabatier, F. Galateau-Sallé
Journal: Annals of Oncology (2005)

Simian virus 40 (SV40) is a monkey virus recently detected in a variety of human cancers such as mesothelioma, central nervous system (CNS) tumours and non-Hodgkin's lymphoma [1.Klein G. Powers A. Croce C. Association of SV40 with human tumors.Oncogene. 2002; 21: 1141-1149Crossref PubMed Scopus (109) Google Scholar]. Despite a large body of data suggesting that SV40 is implicated in different tumours in humans, there are still controversies as to whether SV40 has a role in cancer development [2.Lopez-Rios F. Illei P.B. Rusch V. Ladanyi M. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids.Lancet. 2004; 364: 1157-1166Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 3.J Sabatier, E Uro-Coste, A Benouaich et al. Immunodetection of SV40 large T antigen in human central nervous system tumours. J Clin Pathol, in press.Google Scholar, 4.Brousset P. De Araujo V. Gascoyne R.D. Immunohistochemical investigation of SV40 large T antigen in Hodgkin and non Hodgkin's lymphoma.Int J Cancer. 2004; 112: 533-535Crossref PubMed Scopus (26) Google Scholar]. Morphological methods (in situ hybridization and immunohistochemistry) have been tested in a few studies, which only suggested that the detection of the virus, contrary to other oncogenic viruses, is not reproducible in routine diagnosis. A recent report by Lopez-Rios et al. [2.Lopez-Rios F. Illei P.B. Rusch V. Ladanyi M. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids.Lancet. 2004; 364: 1157-1166Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar] convincingly addressed the issue of SV40 infection in human mesothelioma [2.Lopez-Rios F. Illei P.B. Rusch V. Ladanyi M. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids.Lancet. 2004; 364: 1157-1166Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar]. Their demonstration pointed out a problem of PCR contamination to explain some results. With different approaches, we came to the same conclusion: SV40 has probably little to do with human cancers. Our experience was based on the use of highly sensitive immunohistochemistry with a monoclonal antibody against SV40 large T antigen (T-ag) applied on tissue sections from Hodgkin's and non-Hodgkin's lymphoma and CNS tumours [3.J Sabatier, E Uro-Coste, A Benouaich et al. Immunodetection of SV40 large T antigen in human central nervous system tumours. J Clin Pathol, in press.Google Scholar, 4.Brousset P. De Araujo V. Gascoyne R.D. Immunohistochemical investigation of SV40 large T antigen in Hodgkin and non Hodgkin's lymphoma.Int J Cancer. 2004; 112: 533-535Crossref PubMed Scopus (26) Google Scholar]. In one study [3.J Sabatier, E Uro-Coste, A Benouaich et al. Immunodetection of SV40 large T antigen in human central nervous system tumours. J Clin Pathol, in press.Google Scholar], we failed to detect SV40 T-ag in a series of 82 cases of CNS tumours of various types including plexus choroid tumours and ependymomas. In a second study [4.Brousset P. De Araujo V. Gascoyne R.D. Immunohistochemical investigation of SV40 large T antigen in Hodgkin and non Hodgkin's lymphoma.Int J Cancer. 2004; 112: 533-535Crossref PubMed Scopus (26) Google Scholar], we investigated a series of French and Canadian cases of Hodgkin's and non-Hodgkin's lymphoma with the same technology, i.e. with standard immunohistochemistry and a highly sensitive catalysed system amplification method (CSA™, Dako, Copenhagen, Denmark). The latter technique has, on average, 50-fold greater sensitivity. Again, none of the cases of Hodgkin's lymphoma (n = 250) or non-Hodgkin's lymphoma (n = 232) scored positively, whilst two positive controls were labelled [3.J Sabatier, E Uro-Coste, A Benouaich et al. Immunodetection of SV40 large T antigen in human central nervous system tumours. J Clin Pathol, in press.Google Scholar, 4.Brousset P. De Araujo V. Gascoyne R.D. Immunohistochemical investigation of SV40 large T antigen in Hodgkin and non Hodgkin's lymphoma.Int J Cancer. 2004; 112: 533-535Crossref PubMed Scopus (26) Google Scholar]. To extend our study on SV40, we have tested a series of 100 cases of mesothelioma on standard paraffin sections (n = 65) and tissue microarrays (n = 35). All cases were prepared under the same conditions (fixed 10% buffered formalin and embedded in paraffin). Repeatedly, our results remained negative despite the fact that one-third of the cases had been considered positive with PCR [5.Galateau-Salle F. Bidet P. Iwatsubo Y. et al.SV40-like DNA sequences in pleural mesothelioma, bronchopulmonary carcinoma, and non-malignant pulmonary diseases.J Pathol. 1998; 184: 252-257Crossref PubMed Scopus (71) Google Scholar]. Using tissue array methodology, we then investigated different types of cancers from lung [small-cell carcinoma (n = 15) and non-small-cell carcinoma (n = 43)], digestive tract [gastric adenocarcinoma (n = 13), colon adenocarcinoma (n = 20)], thyroid [papillary carcinoma (n = 30), follicular carcinoma (n = 10)], prostate [adenocarcinoma (n = 21)] and thymus [thymoma (n = 13), thymic carcinoma n = 6)] for SV40 T-ag. Not a single cell could be detected in these tissues. In parallel, we were unable to detect SV40 T-ag in different tissue arrays of normal organs. In particular, we were unable to detect cells infected with the ubiquitous BK virus in normal kidneys (n = 10) and in clear-cell carcinomas (n = 12), since the anti-Tag antibody used cross-reacts with this virus. One important argument against the implication of SV40 in human oncogenesis is that this virus infects monkeys without induction of any type of cancer in this species. Indeed, monkeys are genetically closer to humans than mice. In the latter, the observation of SV40 driven cancers is frequently the result of experiments that induce an up-regulation of viral genes.