No role for simian virus 40 in human pleural mesotheliomas

Mesothelioma is an aggressive cancer of the chest cavity that kills about 2000 people a year in the United States. Seventy to eighty percent of patients with this rare cancer have had exposure to asbestos. It has also been proposed that simian virus 40 (SV40), a contaminant in some polio vaccines administered in the 1950’s and 1960’s, might be a cause. However, studies reporting the detection of SV40 DNA in human tumors (including mesotheliomas, and also some lymphomas, brain cancers, and bone cancers) have not consistently yielded the same results when repeated by other groups. This has fueled an ongoing debate over laboratory methods and the strength of the association of SV40 with these tumors.

A study, published in the September 25 issue of Lancet, calls into question this proposed link between SV40 and pleural mesothelioma and provides a possible explanation for the discrepancies in the results obtained by different groups. Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) used several independent methods to detect SV40 DNA, SV40 RNA, and SV40 proteins in human pleural mesothelioma samples and found no evidence for a significant role for SV40 in human mesotheliomas. Unexpectedly, they found that the SV40 DNA fragments detected in some assays were not derived from genuine SV40 in the tissue samples but from SV40 DNA fragments engineered into common laboratory plasmid vectors used in molecular biology research. This source of SV40 DNA fragments may be unrecognized, leading to misinterpretation of assay results as indicating the presence of genuine SV40 in human tumors. Their findings are a caution to other researchers to be vigilant in avoiding these technical errors when planning future studies with SV40.

“Because SV40 was a recognized contaminant of some polio and adenovirus vaccines in the 50’s and early 60’s, its potential to cause cancer in humans has been a source of intense debate since the apparent detection of SV40 DNA in some human tumors was first reported,” explained Fernando Lopez-Rios, M.D., of the Department of Pathology and the study’s lead author. “An important aspect of our study was that the availability of frozen mesothelioma tumor samples allowed us to search for SV40 RNA (an expected product of functional SV40 DNA), which has never been studied in a large series of mesotheliomas, and to show that it is completely absent.”

Their study presents multiple lines of evidence against the proposed link between SV40 and human mesotheliomas. As part of their ongoing research into the biology of human pleural mesothelioma, this team of MSKCC investigators searched for SV40 DNA, RNA, or protein in frozen tissue samples from 71 human pleural mesotheliomas. According to the study, the methodology used by most researchers for the detection of SV40 DNA is associated with a high risk of false positive results. Therefore, the authors propose that data on SV40 in human tumors need to be carefully re-examined.

“Our previous work on mesothelioma showed that about 80 percent of tumors have lost both copies of the tumor suppressor gene designated p16 or CDKN2A, and this led us to ask whether SV40 infection might be a possible mechanism in the remaining 20 percent,” said Marc Ladanyi, M.D., Director, Diagnostic Molecular Pathology Laboratory, and the study’s senior author. “But instead we found no evidence for SV40 in these tumors and our experiments show for the first time how the assays commonly used to detect SV40 DNA in human tumors are uniquely prone to false-positive results. We hope these results will hasten progress on this deadly cancer.”