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Mulatero et al 1 report failure to detect Simian virus 40 (SV40) DNA in 12 British mesotheliomas. They propose that their negative results indicate that the previous positive findings are probably a consequence of PCR contamination. Since Mulatero et alsubmitted their paper, several laboratories have further confirmed the association of SV40 with human mesothelioma and other types of human tumours.2 ,3 Furthermore, the International Mesothelioma Interest Group has published results of their multilaboratory investigation confirming consistent association of SV40 DNA with mesotheliomas.4 Additional recent studies (reviewed by Butel and Lednicky2) have shown SV40 DNA to exist in an integrated form in human tumours and to be associated with expression of SV40 large T antigen as demonstrated by RNA in situ hybridisation, Western blotting, and immunostaining. These results therefore contradict the PCR contamination theory. The negative findings of Mulatero et al may be explained by technical or demographic differences.2-4 The authors state that the sensitivity of their assay is one SV40 genome per cell based on a PCR methodology capable of detecting HPV. This level of sensitivity is below the threshold for detecting SV40 in human mesothelioma, partly because of the usual low proportion of tumour cells included in mesothelioma biopsy specimens and partly because of the low copy number (<1 copy/tumour cell) of SV40 genome estimated to be associated with this tumour type.2-4 In this context, the adequacy of method sensitivity claimed by the authors based on its comparability with sensitivity of an assay capable of detecting HPV in cervical cancer is potentially misleading. Cervical cancer is not only a more cellular tumour but is known to be associated with several to hundreds of viral genomic copies per tumour cell. We therefore suggest that the specimens of Mulatero et al should be re-tested using a more sensitive methodology to establish whether their negative findings are related to technical or demographic differences.
authors’ reply Dr Jasani misquotes us when he says we suggested that previous positive findings are probably a consequence of PCR contamination; we listed laboratory contamination of samples as one of several possible explanations for differing results.
Dr Jasani suggests that our failure to identify SV40 may be due to inadequate sensitivity and he states that the sensitivity of our assay, which we reported at one copy of SV40 per cell, is below the threshold for detecting SV40 in human mesothelioma. We do not reject the possibility that he may be correct, but he does not identify any evidence to support his assertion. The studies which have identified SV40 in mesothelioma to which he refers, including one of which he was a co-author,1-1 did not report sensitivity of more than one copy per cell.
The multi-institutional study to which Dr Jasani refers1-2examined only 12 cases of mesothelioma from one hospital in New York, but the samples were analysed in four laboratories including one in Finland which had previously reported negative results for SV40 in local mesotheliomas. All four laboratories identified SV40 in 10 of the 12 New York cases. However, in their discussion the authors stated that the Finnish group subsequently confirmed the absence of SV40 in mesothelioma cases from Finland and speculated that this was because SV40 contaminated vaccines had not been used in Finland. This evidence points to demographic differences rather than lack of sensitivity as a more likely explanation for differing results from different series.
It appears from the collective results of various studies that the prevalence of SV40 in mesothelioma may be greater in the USA than in Europe, possibly as a consequence of more widespread use of contaminated polio vaccine in the USA. However, epidemiological evidence indicates that the incidence of mesothelioma in the USA has peaked,1-3 whereas a continuing increase in incidence over the next 20 years is expected in Europe.1-4 These observations, together with evidence that so far there is no increase in the incidence of mesothelioma in individuals who received SV40 contaminated polio vaccine,1-5 do not suggest that SV40 is important in the causation of human mesothelioma.