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SV40 and human cancer: A review of recent data

Corresponding Author

kvshah@jhsph.edu

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Fax: +443-287-4563

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205Search for more papers by this author

Keerti V. Shah,

Corresponding Author

kvshah@jhsph.edu

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Fax: +443-287-4563

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205Search for more papers by this author

First published: 27 November 2006

https://doi.org/10.1002/ijc.22425

Citations: 77

Abstract

An unknown proportion of formalin-inactivated poliovirus vaccine lots administered to millions of US residents between 1955 and 1963 was contaminated with small amounts of infectious simian virus 40 (SV40), a polyomavirus of the rhesus macaque. It has been reported that mesothelioma, brain tumors, osteosarcoma and non-Hodgkin lymphoma (NHL) contain SV40 DNA sequences and that SV40 infection introduced into humans by the vaccine probably contributed to the development of these cancers. The Immunization Safety Review Committee of the Institute of Medicine (IOM) reviewed this topic in 2002. The present review of recent studies showed that the earlier results describing the recovery of SV40 DNA sequences from a large proportion of the above tumors were not reproducible and that most studies were negative. Contamination with laboratory plasmids was identified as a possible source of false positive results in some previous studies. The low-level immunoreactivity of human sera to SV40 was very likely the result of cross-reactivity with antibodies to the SV40-related human polyomaviruses BKV and JCV, rather than of authentic SV40 infection. SV40 sero-reactivity in patients with the suspect tumors was no greater than that in controls. In epidemiologic studies, the increased incidence of some of the suspect tumors in the 1970s to 1980s was not related to the risk of exposure to SV40-contaminated vaccines. In summary, the most recent evidence does not support the notion that SV40 contributed to the development of human cancers. © 2006 Wiley-Liss, Inc.

In 2002, the Immunization Safety Review Committee of the Institute of Medicine (IOM) reviewed the topic of ‘SV40 contamination of polio vaccine and human cancer’ and reported that “The evidence was inadequate to conclude whether or not the contaminated polio vaccine caused cancer.”1 The committee recommended the development and use of sensitive and specific serologic tests for Simian virus 40 (SV40), the development and use of sensitive and specific standardized techniques for SV40 detection, and the study of the transmissibility of SV40 in humans.1 This review presents the perspective of the author who has investigated this question since the mid 1960s.2 The background of the problem is provided first and the discussion is centered primarily on studies published in 2002 and later, in order to evaluate the evidence for an etiologic role of SV40 infection for human cancer. Earlier data are referred to for context and when necessary to make a point. Three questions are addressed: (i) some of the earlier studies reported SV40 DNA sequences (and to a lesser extent SV40 T antigen) in large proportions of mesothelioma, brain tumors, osteosarcoma and non-Hodgkin lymphoma (NHL). Are these results reproducible in the most recent studies? (ii) serology is an independent marker for viral exposure. Is there serological evidence that SV40 is circulating in the human communities or that patients with the suspect cancers are more frequently exposed to SV40? and (iii) the incidence of mesothelioma, brain tumors and NHL increased in the decades following human exposure to SV40 in the contaminated vaccines. Are these 2 events related?

Background

The development and widespread utilization of the injectable formalin-inactivated (Salk) and the orally administered live (Sabin) poliovirus vaccines in the 1950s and 1960s have resulted in spectacular success in the prevention of poliomyelitis, a paralytic disease of childhood which was once one of the most dreaded illnesses in the community. However, the administration of the licensed Salk poliovirus vaccines was accompanied with unanticipated complications. Some lots of the Salk vaccine contained live poliovirus which produced about 200 cases of permanent paralysis and 10 deaths among the vaccinees.3 In another complication (which generated the current controversy), many of the vaccinees were inadvertently exposed to SV40, a polyomavirus indigenous to the rhesus macaque. Cell cultures derived from rhesus kidneys were used to prepare the poliovirus pools for the vaccines, and these kidneys were frequently infected with SV40. The presence of SV40 in the Salk vaccine was not recognized until 1960,4 5 years after the vaccine was licensed in 1955. In the USA, vaccine lots approved in 1961 and later were required to be free of SV40, but lots approved earlier were not recalled, so vaccine-related human exposure to SV40 may have continued until 1963.5 While there is no evidence of SV40 contamination in polio vaccines licensed in the USA and UK after 1961, some vaccines prepared by an eastern European manufacturer contained infectious SV40 until the 1970s.6 The 400,000 US children who received the Salk vaccine in the clinical trial in 1954, as well as the more than 98 million US residents (62% of those under 60 years old and 88% of those under 20 years old) who received 1 or more doses of the commercially licensed Salk vaccine during 1955–1961 were potentially exposed to SV40. Not all vaccine lots during this time period were contaminated with SV40 and, in the contaminated lots, the formalin employed to inactivate polioviruses also inactivated all or most of SV40. Therefore, those vaccinated with the Salk vaccine received no SV40, or only inactivated SV40 or inactivated SV40 along with a small amount of residual live SV40. However, the proportion of the vaccine lots that contained residual live SV40, and the distribution of the amounts of infectious SV40 in these lots, are not known. It is also not known how frequently the individuals who received the small amount of live SV40 in the Salk vaccine by injection became infected. Therefore, the number truly at risk (those infected with SV40) among those potentially exposed to SV40-contaminated Salk vaccine is unknown. The widely used oral polio vaccines were commercially licensed in 1963 and the licensed vaccines were required to be free of SV40, but the few thousand individuals who received the experimental live poliovirus vaccine in earlier clinical trials were at risk of exposure to live SV40 by the oral route. As compared to SV40-contaminated inactivated vaccine, the SV40-contaminated oral vaccines contained a much larger amount of live SV40 because there was no formalin inactivation of the oral vaccine. In addition to exposure by the polio vaccines, several hundred thousand military recruits who were subcutaneously administered formalin-inactivated adenovirus vaccine were also potentially exposed to SV40.7

Some data on the nature of SV40 infection in humans are available. They were derived from studies of stored specimens from previously conducted trials of experimental vaccines in which SV40 was an unrecognized contaminant.5 After intranasal administration, SV40 produced a low-grade infection with virus shedding in the respiratory tract in a few of the volunteers and a low-level antibody response. After oral administration, there was no antibody response but low amounts of the virus were recovered sporadically from stools of some of the vaccinated children. After subcutaneous injection, there was a high-titered antibody response, but it is not known whether the antibody response was a result of infection or to the inactivated SV40 in the vaccine.

In its natural macaque host, SV40 infection is asymptomatic and harmless. But when administered in the laboratory to newborn rodents in high doses, SV40 is oncogenic, and is capable of transforming rodent and human cells in culture. Therefore, the initial major concern was the possibility that SV40 may have produced cancer in the exposed humans.8 Subsequently, a new question was raised. Recovery of SV40 DNA sequences from cancer tissues of children in the USA (born long after the vaccines were required to be free of SV40) implied that the virus had become established in human communities, and that it was circulating by person-to-person transmission and contributing to the development of human cancers.

The debate on the possible adverse effects of SV40 for humans has been contentious.9, 10, 11, 12, 13, 14, 15, 16, 17, 18 High rates of recovery of SV40 DNA sequences from cancer tissues have led some investigators to propose that SV40 infection may have a role in the development of mesothelioma, brain tumors, osteosarcoma and NHL. Other investigators have not been able to confirm the presence of SV40 sequences in the tumors and have been skeptical about the role of SV40 in human cancers.

Presence of SV40 DNA sequences or SV40 T antigen in cancers and other tissues

Studies in 2002 and later that investigated the suspect tumors for SV40 DNA sequences or for SV40 T antigen are summarized in Tables I–III. For discussion, the studies are placed in 1 of 2 categories: (i) completely negative or near-negative (DNA or T antigen prevalence of less than 10%) and (ii) positive (DNA or T antigen prevalence of 10% or greater). Some details of the individual studies are shown in the footnotes to the tables.

Table I. Presence of SV40 DNA Sequences, or SV40 T Antigen, in Mesothelioma (In Articles Published in 2002 and Later)

Reference	Tissue		Method of Detection	Prevalence (%) in tumor
Reference	Origin	State	Method of Detection	Prevalence (%) in tumor
Category 1
Leithner et al.19aa Ten osteosarcomas and 14 giant cell tumors also negative.	Austria	fixed	PCR	0/8
Gordon et al.20bb Less than 1 copy per 100 cells in the two positive tissues.	USA	frozen	QPCR	2/36 (6)
Hubner & Van Marck21cc Some of these tissues had previously tested positive.	Belgium	frozen	PCR	0/12
Mayall et al.22dd 24 tissues from New Zealand, 32 from England.	New Zealand and England	fixed	QPCR	0/56
Lopez-Rios et al.23ee Also negative for SV40 transcripts and SV40 T antigen.	USA	frozen	PCR	0/71
Jin et al.24ff Eight tissues positive by one of three sets of primer pairs; all negative for T antigen.	Japan	fixed	PCR	0/18
Manfredi et al.25gg 16 from Croatia, 11 from South Africa, 26 from UK and 16 from USA; 32 of these also negative for T antigen.	Several	fixed	PCR	0/69
Brousett et al.26	France	fixed	T antigen immunostaining	0/100
Aoe et al.27hh All negative for T antigen.	Japan	fixed	QPCR	2/35 (6)
Total				4/405 (1)
Category 2
DeRienzo et al.28ii 0/9 positive in Turkish and 4/11 in US specimens.	Turkey/USA	fixed	PCR	4/20 (20)
Priftakis et al.29	Sweden	fixed	PCR	3/30 (10)
Cristaudo et al.30jj Sequences also found in 6 of 18 (33%) of bladder cancers.	Italy	fixed	PCR	8/19 (42)
Total				15/69 (22)

a Ten osteosarcomas and 14 giant cell tumors also negative.
b Less than 1 copy per 100 cells in the two positive tissues.
c Some of these tissues had previously tested positive.
d 24 tissues from New Zealand, 32 from England.
e Also negative for SV40 transcripts and SV40 T antigen.
f Eight tissues positive by one of three sets of primer pairs; all negative for T antigen.
g 16 from Croatia, 11 from South Africa, 26 from UK and 16 from USA; 32 of these also negative for T antigen.
h All negative for T antigen.
i 0/9 positive in Turkish and 4/11 in US specimens.
j Sequences also found in 6 of 18 (33%) of bladder cancers.

Table II. Presence of SV40 DNA Sequences, or SV40 T Antigen, in Brain Tumors (In Articles Published in 2002 and Later)

Reference	Tissue		Method of Detection	Prevalence (%) in tumor
Reference	Origin	State	Method of Detection	Prevalence (%) in tumor
Category 1
Kim et al.31aa Tissues of medulloblastoma or supratentorial primitive neuroectodermal tumor (sPNET); these tissues were also negative for BKV and JCV DNA.	USA		PCR	0/20
Engels et al.32bb Ependymomas and choroid plexus papillomas; positive tissue had less than one copy per 100 cells.	India	fixed	QPCR	1/47 (2)
Montesinos-Rongen et al.33cc Primary central nervous system lymphomas in HIV-negative patients.	Germany	fixed	PCR	0/23
Rollison et al.34dd Gliomas, medulloblastomas, meningiomas and choroid plexus tumors. SV40-positive tumors were 2 gliomas and 2 medulloblastomas. One medulloblastoma positive by QPCR had less than one copy per 100 cells.	USA	fixed	PCR and QPCR	4/225 (2)
Sabatier et al.35ee Gliomas, medulloblastomas, meningiomas and choroid plexus tumors.	France	fixed	T antigen immunostaining	0/82
Total				5/397 (1.3)
Category 2
Martini et al.36ff Astrocytoma and glioblastoma; possibility that some of the results were false-positive due to plasmid contamination.	Italy	fixed		10/25 (40)

a Tissues of medulloblastoma or supratentorial primitive neuroectodermal tumor (sPNET); these tissues were also negative for BKV and JCV DNA.
b Ependymomas and choroid plexus papillomas; positive tissue had less than one copy per 100 cells.
c Primary central nervous system lymphomas in HIV-negative patients.
d Gliomas, medulloblastomas, meningiomas and choroid plexus tumors. SV40-positive tumors were 2 gliomas and 2 medulloblastomas. One medulloblastoma positive by QPCR had less than one copy per 100 cells.
e Gliomas, medulloblastomas, meningiomas and choroid plexus tumors.
f Astrocytoma and glioblastoma; possibility that some of the results were false-positive due to plasmid contamination.

Table III. Presence of SV40 DNA or SV40 T Antigen in Non-Hodgkin Lymphoma (In Articles Published in 2002 and Later)

Reference	Tissue		Method of Detection	Prevalence (%) in tumor
Reference	Origin	State	Method of Detection	Prevalence (%) in tumor
Category 1
Capelio et al.37aa None positive by all three primer pair sets used.	Italy and Spain	Frozen	PCR	0/346
MacKenzie et al.38bb An additional 107 specimens of lymphoid disorders also negative for SV40. All specimens negative for BKV and JCV.	UK	Frozen	PCR and QPCR	0/152
Daibata et al.39	Japan	Frozen, fixed	PCR	3/178 (1.7)
Brousset et al.40cc 250 cases of Hodgkin lymphomas also negative by T antigen immunostaining.	France and Canada	Fixed	T antigen immunostaining	0/232
Sui et al.41dd Lymph nodes from 5 cases of Hodgkin lymphoma and from 50 controls (some with other cancers) also negative.	Australia	Fixed	PCR	0/45
Schuler et al.42ee Specimens from 6 Hodgkin lymphoma patients and 45 normal individuals also negative.	Germany	Fresh	QPCR	0/95
Total				3/1048 (0.3)
Category 2
Vilchez et al.43ff Similar prevalence in HIV− and HIV+ patients. Most cases in diffuse large cell and follicular subtypes.	USA	Not stated	PCR	64/154 (42)
Shivapurkar et al.44gg Also found in 3 of 31 (9%) Hodgkin lymphoma and in about 5% of epithelial tumors.	USA	Frozen, fixed	PCR	29/68 (43)
Nakatsuka et al.45hh In previous study, 4.7% prevalence in peripheral blood cells of normal individuals.	Japan	Frozen	PCR	14/122 (11)
Shivapurkar et al.46ii Aberrant methylation of tumor suppressor genes associated with SV40 positivity.	USA	Not stated	PCR and QPCR	33/90 (37)
Meneses et al.47jj Blinded study, 2 of 19 (10%) Hodgkin lymphoma also positive. 91 control tissues negative for SV40 DNA. T antigen detected in 18 of 28 (64%) SV40 DNA positive and in none of 16 SV40 DNA negative tissues.	Costa Rica	Fixed	PCR	28/106 (26)
Total				168/540 (31)

a None positive by all three primer pair sets used.
b An additional 107 specimens of lymphoid disorders also negative for SV40. All specimens negative for BKV and JCV.
c 250 cases of Hodgkin lymphomas also negative by T antigen immunostaining.
d Lymph nodes from 5 cases of Hodgkin lymphoma and from 50 controls (some with other cancers) also negative.
e Specimens from 6 Hodgkin lymphoma patients and 45 normal individuals also negative.
f Similar prevalence in HIV− and HIV+ patients. Most cases in diffuse large cell and follicular subtypes.
g Also found in 3 of 31 (9%) Hodgkin lymphoma and in about 5% of epithelial tumors.
h In previous study, 4.7% prevalence in peripheral blood cells of normal individuals.
i Aberrant methylation of tumor suppressor genes associated with SV40 positivity.
j Blinded study, 2 of 19 (10%) Hodgkin lymphoma also positive. 91 control tissues negative for SV40 DNA. T antigen detected in 18 of 28 (64%) SV40 DNA positive and in none of 16 SV40 DNA negative tissues.

Prevalence in cancers

Mesothelioma.

In 1994, Carbone et al.48 reported the detection of SV40 sequences in 60% of human mesothelioma, a rare tumor related to exposure to asbestos, and suggested that the SV40-contaminated poliovaccines may have been the source of infection of humans. This tumor is one of the most intensively investigated for its association with SV40 and the evidence for the role of SV40 in tumor development is considered the strongest for mesothelioma.11 The IOM report listed 29 studies in which mesothelioma tissues were tested for SV40 DNA sequences, with the reported prevalence ranging from 0 to 100%.1

The SV40-mesothelioma association was investigated in 12 studies in 2002 and subsequent years (Table I). Nine of these studies were in Category 1 (completely negative or near-negative), and combined, report on 405 mesothelioma tissues with 4 (1%) found to be SV40-positive. The other 3 studies, combined, report on 69 tissues with 15 (22%) found to be positive. The geographic origin of the tissues was similar for the positive and the negative studies, and tissues from USA and Europe contributed positive as well as negative samples.

Among the negative studies, Gordon et al.20 were the first to employ quantitative SV40 PCR for mesothelioma tissues. They reported 2 of 35 tissues as positive, with estimates of less than 1 copy of SV40 sequence for 100 tumor cells and concluded that SV40 was not a contributing factor for most of the tumors. Mayall et al.22 and Aoe et al.27 also employed quantitative PCR with essentially negative results. Hubner and Van Marck21 retested frozen tissues employing 5 extraction methods and 4 primer pairs and failed to detect SV40 sequences in any of the tissues. Many of these tissues were previously reported as positive. Jin et al.24 tested tumors from Japan with 3 sets of primer pairs targeting DNA in the SV40 T antigen region; sequences were detected in a proportion of the samples with 1 primer pair set, but all tissues were negative with the other 2 primer pair sets. All of the tissues were also negative for T antigen by immunostaining. Manfredi et al.25 failed to detect SV40 sequences or SV40 T antigen in mesotheliomas from 4 different geographic regions. They concluded that their results strongly argue against an etiologic role for SV40 in mesothelioma. Brousset et al.26 failed to detect SV40 T antigen in mesothelioma specimens by immunohistochemistry with a highly sensitive method despite the fact that one-third of the tested specimens were reported to contain SV40 DNA sequences in an earlier investigation.49 The authors concluded that SV40 probably has little to do with human cancer.

In 1 of the Category 1 studies, Lopez-Rios et al.23 definitively identified contamination with laboratory plasmids as a source for false positive data in SV40 PCR. This possibility was raised during the early discussions of the SV40 controversy.50, 51 Lopez-Rios et al.23 were investigating if homozygous deletion of the 9p21 locus (seen in a majority of mesotheliomas) and the presence of SV40 T antigen were alternative mechanisms for the inactivation of the p53 and Rb pathways in this cancer. They tested the tissues for SV40 sequences employing 2 sets of primers targeting the region of the SV40 genome that encodes the Rb-pocket binding domain of T antigen and obtained positive results for 56–62% of the tissues, a prevalence comparable to that in earlier positive studies of mesothelioma. However, the 2 primer pairs, although they targeted almost identical sequences, gave 20% discordant results, and an occasional ‘no DNA’ control was positive. The T antigen gene sequence amplified by the 2 primer sets was within the region of the SV40 genome (nucleotides 4,100–4,713) that is included in many common laboratory-engineered plasmids. The investigators therefore conducted additional tests with a primer pair targeting a fragment not encompassed in the region 4,100–4,713 and found that the mesothelioma tissues were essentially negative for SV40 DNA. They also found the tissues negative for SV40 transcripts and SV40 T antigen. The authors then confirmed that the SV40 sequences in the previously positive samples had a deletion found only in the plasmids and not present in wild type SV40 DNA. In addition, in a review of the literature, they identified a previously published study36 in which a similar inadvertent contamination with laboratory plasmids appeared to have generated false-positive data. They concluded that primers targeting sequences in the 4,100–4,713 region of SV40 were at ‘high-risk’ for providing false-positive data as a result of plasmid contamination. Although it is not known to what extent plasmid contamination contributed to positive data in other studies, it is worthy of note that almost all the PCR studies to date for SV40 DNA have employed ‘high-risk’ primers.

Among the 3 positive studies, DeRienzo et al.28 found SV40 DNA sequences in tumors from USA but not in tumors from Turkey. Ten percent of tumors from Sweden were positive.29 Cristaudo et al.30 recovered SV40 sequences not only from mesothelioma but also, at about the same frequency, from bladder cancers which they had chosen as ‘controls’, because bladder cancer was not previously associated with SV40.

Brain tumors.

The article by Bergsagel et al.52 in 1992 reporting the presence of SV40 DNA sequences in pediatric brain tumors (ependymoma and choroid plexus tumors) was the first PCR-based investigation to identify SV40 DNA in human tumors. In subsequent studies, SV40 DNA has been reported from brain tumors of both adult and pediatric patients, and representing brain tumors of many histologic types.53

Three of the 6 studies on SV40 and brain tumors published in 2002 or later were completely negative and each of 2 additional studies had an SV40 DNA prevalence of 2% (Table II). These 5 studies in Category 1, combined, represent tests on 397 brain tumors with a 1.3% prevalence of SV40 DNA. The single study with positive data describes 25 cases of which 10 (40%) were reported to contain SV40 DNA. In addition to these 6 studies, there was a report describing an unusual case of a laboratory scientist who had worked with an SV40-transformed cell line in the laboratory and had developed a meningioma which contained SV40 DNA sequences.55 After a comparison of the SV40 sequences in the patient's tumor and in the cell line, the authors concluded that the scientist's tumor may have resulted from exposure to SV40 in the laboratory.

Among the studies in Category 1, the 1 SV40-positive tissue in the study of ependymomas and choroid plexus tumors from India32 was estimated to contain less than 1 copy per 100 cells. Rollison et al.34 examined over 200 brain tumors for SV40, BKV and JCV sequences independently in 2 laboratories, one of which employed conventional PCR and the other quantitative PCR. SV40 sequences were detected in 4 tissues, including 2 astrocytomas and 2 medulloblastomas. None of the tissues were positive in both laboratories. Only 1 tissue, a medulloblastoma, was positive by quantitative PCR and it was estimated to contain less than 1 copy of SV40 DNA per 100 cells. The other 3 negative studies reported on tumors from USA,31 Germany33 and France.35

In the single study in Category 2, Martini et al.36 reported SV40 DNA sequences from 10 of 25 gliomas, 21 of 69 bone tumors and 11 of 38 buffy coats of normal individuals. It is probable that some of these results were false positives. In several instances, the PCR amplification products in these tests were about 500 bp long rather than the anticipated 1,847 bp product targeted by the primers. It has been suggested that the investigators may have amplified the shorter sequences from a contaminating laboratory expression plasmid that contained SV40 sequences with an engineered deletion of 1,329 bp.23

Osteosarcoma.

Two studies of osteosarcoma were published, 1 of Category 1 and 1 of Category 2. As mentioned in the footnote of Table I, Leithner et al.19 failed to detect SV40 DNA sequences in 10 osteosarcoma and 14 giant cell tumors from Austria.

In a 2002 publication, Martini et al.36 reported SV40 DNA sequences in 15 of 41 (37%) osteosarcoma tissues from Italy. It is probable that some of these results are false positives due to contamination with a laboratory plasmid,23 for reasons discussed in the last paragraph in the earlier discussion of brain tumors.

Non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) encompasses a biologically diverse group of tumors of several different histological subtypes and includes both B cell and T cell malignancies. The proposed association of SV40 with NHL took center stage in this controversy with the publication of 2 articles in the Lancet in 2002 from 2 US laboratories which reported that 42–43% of NHL contained SV40 DNA sequences.43, 44 Three previous studies had reported SV40 DNA in a smaller proportion of NHL. Of the eleven studies published in 2002 or later (Table III), 6 were in Category 1; with 5 reporting negative data and 1 reporting a low prevalence of 1.7%.39 These 6 studies, combined, reported tests on 1,048 specimens, with SV40 DNA prevalence of 0.3%. The 5 studies in Category 2 (which include the 2 2002 Lancet studies and 2 additional studies from the same laboratories46, 47), reported tests on 540 specimens of which 168 (31%) were positive for SV40 DNA. Two negative studies of NHL, 1 describing CNS lymphomas33 (listed in Table II) and the other describing cutaneous lymphomas56 are not included in Table III because CNS and cutaneous NHLs were not examined in the 2002 Lancet studies.

Among the studies in Category 1, Capello et al.37 tested 500 specimens from lymphoproliferative disorders from Spain and Italy for SV40 DNA by 3 primer pair sets; none were positive by all three, but 17 (3.4 %) were positive by 2 primer sets. Of these 500 specimens, 346 were from NHL cases (Guidano, personal communication). In cases of NHL in the UK, MacKenzie et al.38 failed to detect SV40 DNA by quantitative PCR and SV40, BKV or JCV DNA by a consensus PCR. Daibata et al.39 reported 1.7% prevalence in Japanese specimens. Brousset et al.40 did not detect SV40 T antigen by immunostaining in NHL or HL from France and Canada. Sui et al.41 did not detect SV40 DNA in lymph nodes of NHL patients or of controls from Australia. Schuler et al.42 did not detect SV40 DNA in NHL or normal tissues from Germany.

In category 2 studies, Vilchez et al.43 found similar prevalences of SV40 DNA in NHLs of HIV-infected and HIV-uninfected patients in the USA and did not detect SV40 DNA in over 200 control specimens. In a blinded study by the same laboratory in Costa Rica, Meneses et al.47 found SV40 DNA in 26% of NHL and in none of controls, and SV40 T antigen in 64% of SV40 DNA-positive vs. 0% of SV40-negative NHL. The detection of SV40 DNA only in cases, and the detection of T antigen only in DNA positive cases, shows an internal consistency in these results.

Shivapurkar et al.44 found SV40 DNA in 43% of NHLs but also in about 5% of pediatric and adult epithelial cancers. Pediatric cancers which were sometimes positive for SV40 included Wilm's tumor, hepatoblastoma, rhabdomyosarcoma, medulloblastoma, osteosarcoma and retinoblastoma. Adult cancers that sometimes contained SV40 DNA included lung, breast, colon and prostate carcinoma. In another study, Shivapurkar et al.46 compared SV40-negative NHL with SV40-positive NHL and reported that the presence of SV40 in hematological malignancies was associated with promoter methylation of tumor suppressor genes. In a study of Japanese NHL, Nakatsuka et al.45 reported an SV40 DNA prevalence of 11%.

Evaluation of the PCR assays

As discussed above, SV40 DNA sequences have been recovered not only from the suspect cancers but at low frequencies from 10 other cancers46 and from bladder tumors.30 Others have reported SV40 DNA sequences in thyroid nodules,57 in hepatocellular carcinoma58 and in genital tract tumors.59 SV40 DNA has been reported to be present36, 53, 60, 61 or absent43, 62, 63 in kidney disease, in urine and in peripheral blood cells of normal individuals.

The wide discordance in results from the various laboratories and the recovery of SV40 DNA from so many dissimilar sites has led to evaluations of the PCR assays for sensitivity and specificity. In one such study sponsored by the National Institutes of Health and the Food and Drug Administration, this question was addressed in a methodologically rigorous way.64 Nine laboratories participated in tests of masked mesothelioma (25 tissues each tested in duplicate) and control (25 normal lung) specimens and of masked panels of positive and negative controls. Seven laboratories successfully used an agreed upon common PCR assay as well as other PCR assays of their choosing to detect SV40 DNA sequences. Five of the 7 laboratories consistently detected 50 copies of the sequences, an indication that the analytical sensitivity of the assay was adequate. The combined results of the 7 laboratories for detection of SV40 DNA with the common assay are shown in Table IV. SV40 sequences were detected at similar low frequencies (2.3–5.7%) from mesothelioma, normal lung and negative controls. A single mesothelioma specimen was scored as positive in both duplicate samples in only one of the 7 laboratories. That specimen was not found to be positive in any of the 12 tests in the other 6 laboratories. The study revealed additional examples of laboratory problems. The results from one laboratory were excluded because the investigator reported that the primers employed for the PCR assay were contaminated with SV40 sequences. When the study results were unmasked, it was discovered that one of the 2 batches of negative controls (provided by an outside laboratory) was contaminated with SV40 at the source of origin. The results of this investigation showed that mesothelioma specimens were not reproducibly positive for SV40 DNA and exemplified how false positive data commonly plague the PCR technology.

Table IV. Frequency of Detection of SV40 DNA Sequences in the NIH-FDA Study64

	Number of Assays	Percent positive for SV40 DNA
Mesotheliomaaa 25 tissues, in duplicate, in seven laboratories.	350	2.6
Normal lungbb 25 tissues in seven laboratories.	175	2.3
Negative controlcc 5 samples in specificity panel, in seven laboratories.	35	5.7

a 25 tissues, in duplicate, in seven laboratories.
b 25 tissues in seven laboratories.
c 5 samples in specificity panel, in seven laboratories.

SV40 antibody seroprevalence in the community and in cancer cases

The presence of serum antibodies is a sensitive and specific marker of virus infection and can therefore contribute to the resolution of the controversy about the specificity of the reported recovery of SV40 sequences from human tissues. If SV40 is circulating in the community by person-to-person transmission, SV40-specific antibodies should be detected in serological surveys; and if SV40 infection is associated with a particular cancer, serological evidence of infection with SV40 should be more frequent in patients with the suspect cancer, as compared with cancer-free controls. The IOM Report in 2002 emphasized the potential benefits of serologic investigations and strongly recommended expansion of these studies.1

Serologic data have been recently reviewed.65 In contrast to the SV40 DNA studies that gave widely contradictory data in the different laboratories, the results of serologic studies have been comparable across the field. They show a low-level immunoreactivity of human sera to SV40, confirming earlier observations made in the 1960s.2 They also address the question of whether this low level immunoreactivity to SV40 is indicative of past SV40 infection or if it results from cross-reactivity with antibodies to the related human polyomaviruses BKV and JCV. In addition, the studies examine if sera from patients with mesothelioma, brain tumors, osteosarcoma and NHL are more immunoreactive with SV40 than the sera of controls.

Serological cross reactivity between SV40 and human polyomaviruses BKV and JCV

Enzyme immunoassays (EIA) of the sera of rhesus macaque with virus-like particles (VLPs) of SV40, BKV and JCV provide unambiguous evidence of immunologic cross reactivity among these viruses66 (Fig. 1). Rhesus sera which were negative for SV40 by plaque neutralization tests were completely nonreactive with all 3 VLPs. In contrast, sera that were positive for SV40 antibodies were not only strongly reactive, as expected, with SV40 VLPs, but were also reactive, to a lesser extent, with BKV and JCV VLPs. Competitive inhibition studies showed that the reactivity of these sera to BKV and JCV was completely eliminated by prior incubation with SV40 VLPs, indicating that the BKV and JCV reactivity of these sera was a result of cross-reactivity with SV40 antibodies.67

**Figure 1**
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Reactivity of SV40 neutralizing antibody negative (n = 17, Panel A) and antibody positive (n = 39, Panel B) rhesus macaque sera to SV40, BKV and JCV VLPs in enzyme immunoassay. From Viscidi *et al.*, Clin Diagn Lab Immunol, 2003, 10, 278–85, © American Society for Microbiology, reproduced by permission.

The pattern of immunoreactivity of human sera to BKV, JCV and SV40 is illustrated in a study of over 2,400 human sera from England68 (Fig. 2). The overall seroprevalence of 3.2% for SV40 was low as compared to 81% for BKV and 35% for JCV, and it did not increase with age. The neutralizing antibody titers of the SV40-positive sera were low. SV40 immunoreactivity was associated with antibodies to BKV and JCV. SV40 was neutralized significantly more frequently by BKV antibody-positive sera than by BKV antibody-negative sera (3.8% vs. 0.9%, p < 0.001) and also by JCV antibody-positive sera than by JCV antibody-negative sera (4.5% vs. 2.5%, p < 0.001). Only 1 of the 79 sera with SV40 antibodies was negative for both BKV and JCV. Very similar correlations between SV40 antibodies and BKV and JCV antibodies were reported in studies in the USA in which sera were tested by EIA employing virus-like particles (VLPs) of BKV, JCV and SV40 as antigen.66

**Figure 2**
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Age-specific seroprevalence of BKV, JCV and SV40 antibodies in England, 1991. From Knowles *et al.*, J Med Virol, 2003, 71, 115–23, © Wiley-Liss, reproduced by permission.

The nature of this SV40 immunoreactivity was further examined by competitive inhibition studies in which SV40-reactive human sera were pre-incubated with VLPs of BKV, JCV and SV40 and then tested for SV40 reactivity by EIA. A single concentration of BKV VLPs inhibited SV40 immunoreactivity of the human sera by 29–61% (median 42%).70 In another study,69 pre-incubation of SV40-reactive human sera with increasing concentrations of BKV or JCV VLPs completely inhibited their SV40 reactivity, indicating that the SV40 reactivity of these sera was the result of cross-reactivity with BKV and JCV antibodies. In the discussion of their serologic data, Carter et al.69 state that “It would be unusual for SV40 infection levels to be so low that they fail to generate a detectable immune response, yet produce enough virus to be widely transmitted”.

SV40 seroreactivity in cancer cases and controls

The data on SV40 seroreactivity of cancer cases and controls are summarized in Table V. The prevalence of SV40 neutralizing antibodies was low and similar for mesothelioma cases, osteosarcoma cases and for controls age-matched to mesothelioma cases.71 Carter et al.69 reported 2.5% of sera from osteosarcoma cases and 7.7% of sera from controls as immunoreactive with SV40 VLPs in EIA. Rollison et al.72, 73 conducted case-control studies, nested within a prospective cohort, to investigate if antibodies to SV40 in sera collected prior to the diagnoses of brain tumors or NHL were associated with incident cases of these cancers. The prevalence of neutralizing antibodies in prediagnostic sera of brain tumor cases was identical to that in control sera.72 For NHL, the prevalence of SV40 antibodies by VLP EIA was higher in prediagnostic sera of cases than in controls (15% vs. 10%, matched odds ratio (OR), 1.97; 95% confidence interval (CI), 1.03–3.76).73 However, the SV40 immunoreactivity of 85% of the SV40 VLP-reactive sera of NHL cases and controls was decreased by pre-incubation with a single concentration of BKV or JCV VLPs and antibodies specific for SV40 (SV40 reactivity that was competitively inhibited >50% by SV40 and <50% by both BKV and JCV) were identified in only 1.8% of cases and 1.6% of controls (OR, 1.51; 95% CI, O.41–5.52). In a case-control study of incident lymphoma cases in Spain, Sanjose et al.70 reported immunoreactivity to SV40 VLPs in 5.9% of cases and 9.5% of controls. There was no association of SV40 positivity with any of the lymphoma histological subtypes including those that are classified as NHL. Engels et al.74 conducted a case-control study of population-based incident US cases of NHL in which 2 independent laboratories tested sera for SV40 immunoreactivity by VLP EIA. SV40 antibody results from the 2 laboratories were correlated. The SV40 antibody prevalence was 7.2% in cases and 10.5% in controls in 1 laboratory, and 9.8% in cases and 9.6% in controls in the other laboratory. After competitive inhibition assays, only a small proportion of the SV40-immunoreactive sera was considered to have SV40-specific antibodies. A subset of the sera tested in this investigation, which included all available sera which were immunoreactive with SV40 VLPs, was also tested for immunoreactivity to full length purified SV40 large T antigen in EIA.75 Low levels of T antibodies were detected in 10 sera, in 5.8% of cases and 5.2% of controls. All of the 10 human sera had low levels of SV40 T antigen-reactive antibodies and they were also reactive with BKV VLPs, suggesting that they might represent cross-reactivity to BKV T antigen.76

Table V. Prevalence of SV40 Seroreactivity in Cancer Cases and Controls

Cancer	Assay	Prevalence (%)		Reference
Cancer	Assay	Cases	Controls	Reference
Mesothelioma	Plaque neutr	3/34 (8.8)	1/35 (2.9)	Strickler et al.71
Osteosarcoma	Plaque neutr, VLP, EIA	1/34 (3.3)	1/35 (2.9)	Strickler et al.71
Osteosarcoma		3/122 (2.5)	32/415 (7.7)	Carter et al.69
Brain tumoraa In these two studies, the sera of cases were collected prior to the diagnosis of the cancers; in all other studies, the sera were collected from cases with the cancers.	Plaque neutr	5/44 (11.4)	10/88 (11/4)	Rollison et al.72
NHLaa In these two studies, the sera of cases were collected prior to the diagnosis of the cancers; in all other studies, the sera were collected from cases with the cancers.	VLP EIA	33/217 (15.2)	41/434 (9.5)	Rollison et al.73
Lymphoma	VLP EIA	31/520 (5.9)	56/587 (9.5)	Sanjose et al.70
NHL	VLP EIA, lab A	52/724 (7.2)	65/622 (10.5)	Engels et al.74
NHL	VLP EIA, lab B	70/718 (9.8)	59/615 (9.6)	Engels et al.74
NHL	T antigen EIA	5/85 (5.8)	5/95 (5.2)	Engels et al.75

a In these two studies, the sera of cases were collected prior to the diagnosis of the cancers; in all other studies, the sera were collected from cases with the cancers.

These studies clearly indicate that immunoreactivity to SV40 was no more frequent in sera of patients with suspect tumors than in sera of controls, and provide no serological evidence for an association of the cancers with exposure to SV40.

Risk of cancers in populations exposed to SV40-contaminated vaccines

This question has been addressed in 4 epidemiologic studies published after the IOM report. In 2 of these studies, the exposure to SV40-contaminated vaccine was more uniform than that in the US residents who received the inactivated poliovaccine. Several hundred thousand US military recruits who entered service in 1959–1961 and received an inactivated adenovirus vaccine were very probably all exposed to SV40-contaminated vaccine.77 The SV40 concentration in this vaccine was high because the adenovirus pools were prepared in rhesus kidney cultures, and adenoviruses grow well in these cells only when they are coinfected with SV40. A case-control study of cancer among these US army veterans did not show an increased risk of brain tumors and NHL in the vaccine recipients.77 Similarly, those who received polio vaccines in 1955–1962 in Denmark were more uniformly exposed to SV40 than those in the US because all of the vaccine lots administered in Denmark during this time period were shown to contain live residual SV40, and nearly 100% of the children received the vaccine.78 In an analysis of cancer incidence data from the Danish Cancer Registry over a 55-year period, there was no evidence that exposure to SV40 in contaminated polio vaccines as infants or as children was associated with an increased risk of mesothelioma, brain tumors or NHL.

The other 2 studies were age-period-cohort analyses of the US and Norwegian populations. Strickler et al.79 noted that the probability of having received contaminated vaccine in the USA differed by age and examined if the incidence rates of pleural mesothelioma between 1975 and 1997 were higher in birth cohorts that had a higher risk of having received contaminated vaccine. Several thousand cases of pleural mesothelioma cases were recorded in this time period. They found that pleural mesothelioma incidence declined or remained stable in the younger age groups, which had a high probability of having received contaminated vaccine, but it increased in the oldest age groups which had a low probability of having received contaminated vaccine. In an age-period-cohort analysis, which allows one to distinguish between time period and birth cohort as explanatory variables for the temporal changes in cancer incidence rates, they found that the incidence rates of pleural mesothelioma were unrelated to level of exposure to SV40-contaminated vaccine. They also noted that following exposure to SV40-contaminated vaccine, which was the same for men and women, there was no acceleration of the incidence of mesothelioma in women, an indication that SV40 was not an independent risk factor for mesothelioma.79 Similarly, in an age-period-cohort analysis of Norwegian data, Thu et al.80 did not find an association between exposure to SV40-contaminated polio vaccine in 1956–1963 and the increase in NHL incidence rates in the following decades.

Comments and conclusions

Three questions were addressed in this review. With respect to the prevalence of SV40 DNA and SV40 T antigen in the suspect cancers, 21 of the 31 studies in 2002 and later were negative or near-negative. Most of the 10 positive studies came from a small number of highly prolific laboratories. Not a single recent study of mesothelioma, brain tumors and osteosarcoma had convincingly positive results. In studies of NHL, there were clearly negative and clearly positive studies. In the few positive cancers in which the amount of SV40 DNA was estimated by quantitative PCR, the amount was so small that it ruled out the possibility that the tumor had arisen by clonal expansion of SV40-transformed cells. Contamination with laboratory plasmids was definitively identified as a possible source of false-positive results in some of the previous positive studies. At a minimum, it can be concluded that the results of the earlier studies in which 30–50% of the cancers were found to be SV40-positive, are not reproducible. With respect to the second question, serological data did not support the notion that SV40 has become established as a human infection and was circulating in the community by person to person contact or that patients with the suspect cancers had greater exposure to the virus than controls. The low level reactivity of human sera to SV40 was largely, perhaps completely, the result of cross-reactivity to the related human polyomaviruses BKV and JCV. With respect to the third question, the possibility that the increasing incidence of mesothelioma, brain tumors and NHL in the decades following vaccination might be related to exposure to SV40 in contaminated vaccines seemed plausible when SV40 DNA sequences were identified in these cancers.11, 81 There is no evidence that this is the case. All 4 epidemiologic studies discussed in this review concluded, as had earlier studies,1 that the increased incidence of the cancers did not occur in those who had the highest risk of SV40 exposure from contaminated vaccine. As emphasized in the IOM report,1 these data by themselves do not disprove the role of SV40 in human cancer because the exposure to SV40 by the vaccine is not known at the level of the individual, but they do allow the more limited interpretation that the increased incidence of cancers was unrelated to the contaminated vaccine.

It is very likely that SV40 infections are not prevalent in human communities and are not linked to any human cancer. However, in order to maintain public confidence in vaccines, legitimate questions related to vaccine safety must be answered as fully as possible. The collective experience of the field suggests that future studies should incorporate the following features: (i) blinded design; (ii) tests of suspect cancer tissues as well as negative tissues; (iii) employment of several primer pairs targeting different regions of the SV40 genome; (iv) quantitative PCR; (v) blinded panels for estimating sensitivity and specificity of the PCR essays; (vi) tests for SV40 transcripts and for SV40 T antigen; and (vii) tests of the sera of cancer cases and controls (donors of tissues tested for SV40 DNA sequences) for antibodies to SV40 VLPs and SV40 T antigen. It would be helpful if the IOM would revisit this issue to provide an updated report and to recommend what more needs to be done to resolve this controversy.

Acknowledgements

The author has served as a consultant to pharmaceutical companies and has been compensated for his time.

References

1 Stratton K, Almario DA, McCormick MC. Immunization safety review: SV40 contamination of polio vaccine and cancer. Washington DC: National Academy Press, 2002.
Web of Science®Google Scholar
2 Shah KV. Neutralizing antibodies to Simian virus 40 (SV40) in human sera from India. Proc Soc Exp Biol Med 1966; 121: 303– 7.
Crossref PubMed Web of Science®Google Scholar
3 Offit P. The Cutter incident. New Haven: Yale University Press, 2005.
Google Scholar
4 Sweet BH, Hilleman MR. The vacuolating virus, SV40. Proc Soc Exp Biol Med 1960; 105: 420– 7.
Crossref PubMed Web of Science®Google Scholar
5 Shah KV, Nathanson N. Human exposure to SV40: review and comment. Am J Epidemiol 1976; 103: 1– 12.
Crossref CAS PubMed Web of Science®Google Scholar
6 Cutrone R, Lednicky J, Dunn G, Rizzo P, Bocchetta M, Chumakov K, Minor P, Carbone M. Some oral poliovirus vaccines were contaminated with infectious SV40 after 1961. Cancer Res 2005; 65: 10273– 9.
Crossref CAS PubMed Web of Science®Google Scholar
7 Sherwood RW, Buescher EL, Nitz RE, Cooch JW. Effects of adenovirus vaccine on acute respiratory disease in U.S. Army recruits. JAMA 1961; 178: 1125– 7.
Crossref CAS PubMed Web of Science®Google Scholar
8 Fraumeni JF, Ederer F, Miller RW. An evaluation of the carcinogenicity of simian virus 40 in man. J Am Med Assoc 1963; 185: 713– 18.
Crossref PubMed Web of Science®Google Scholar
9 Vilchez RA, Butel JS. Emergent human pathogen simian virus 40 and its role in cancer. Clin Microbiol Rev 2004; 17: 495– 508.
Crossref CAS PubMed Web of Science®Google Scholar
10 Garcea RL, Imperiale MJ. Simian virus 40 infection of humans. J Virol 2003; 77: 5039– 45.
Crossref CAS PubMed Web of Science®Google Scholar
11 Gazdar AF, Butel JS, Carbone M. SV40 and human tumours: myth, association or causality? Nat Rev Cancer 2002; 2: 957– 64.
Crossref CAS PubMed Web of Science®Google Scholar
12 Strickler HD. Simian virus 40 (SV40) and human cancers. Einstein Q J Biol Med 2001; 18: 14– 20.
Google Scholar
13 Barbanti-Brodano G, Sabbioni S, Martini F, Negrini M, Corallini A, Tognon M. BK virus, JC virus and simian virus 40 infection in humans, and association with human tumors. In: N Ahsan, ed. Polyomaviruses and human diseases. Georgetown, TX: Landes Bioscience, 2006; 319– 41.
Crossref Web of Science®Google Scholar
14 DE Rollison. Epidemiological studies of polyomaviruses and cancer: previous findings, methodologic challenges and future directions. In: N Ahsan, ed. Polyomaviruses and human diseases. Georgetown, TX: Landes Bioscience, 2006; 342– 56.
Google Scholar
15 Dang-Tan T, Mahmud SM, Puntoni R, Franco EL. Polio vaccines, Simian virus 40, and human cancer: the epidemiologic evidence for a causal association. Oncogene 2004; 23: 6535– 40.
Crossref CAS PubMed Web of Science®Google Scholar
16 Shah KV. Does SV40 infection contribute to the development of human cancers? Rev Med Virol 2000; 10: 31– 43.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
17 Engels EA. Does simian virus 40 cause non-Hodgkin lymphoma? A review of the laboratory and epidemiological evidence. Cancer Invest 2005; 23: 529– 36.
Crossref CAS PubMed Web of Science®Google Scholar
18 Magnani C. SV40, genetic polymorphism and mesothelioma. Pathological and epidemiological evidence. Med Lav 2005; 96: 347– 53.
CAS PubMed Google Scholar
19 Leithner A, Weinhaeusel A, Windhager R, Schlegl R, Waldner P, Lang S, Dominkus M, Zoubek A, Popper HH, Haas OA. Absence of SV40 in Austrian tumors correlates with low incidence of mesotheliomas. Cancer Biol Ther 2002; 1: 375– 9.
Crossref CAS PubMed Web of Science®Google Scholar
20 Gordon GJ, Chen CJ, Jaklitsch MT, Richards WG, Sugarbaker DJ, Bueno R. Detection and quantification of SV40 large T-antigen DNA in mesothelioma tissues and cell lines. Oncol Rep 2002; 9: 631– 4.
CAS PubMed Web of Science®Google Scholar
21 Hubner R, Van Marck E. Reappraisal of the strong association between simian virus 40 and human malignant mesothelioma of the pleura (Belgium). Cancer Causes Control 2002; 13: 121– 9.
Crossref PubMed Web of Science®Google Scholar
22 Mayall F, Barratt K, Shanks J. The detection of Simian virus 40 in mesotheliomas from New Zealand and England using real time FRET probe PCR protocols. J Clin Pathol 2003; 56: 728– 30.
Crossref CAS PubMed Web of Science®Google Scholar
23 Lopez-Rios F, Illei PB, 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– 66.
Crossref CAS PubMed Web of Science®Google Scholar
24 Jin M, Sawa H, Suzuki T, Shimizu K, Makino Y, Tanaka S, Nojima T, Fujioka Y, Asamoto M, Suko N, Fujita M, Nagashima K. Investigation of simian virus 40 large T antigen in 18 autopsied malignant mesothelioma patients in Japan. J Med Virol 2004; 74: 668– 76.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
25 Manfredi JJ, Dong J, Liu WJ, Resnick-Silverman L, Qiao R, Chahinian P, Saric M, Gibbs AR, Phillips JI, Murray J, Axten CW, Nolan RP, et al. Evidence against a role for SV40 in human mesothelioma. Cancer Res 2005; 65: 2602– 9.
Crossref CAS PubMed Web of Science®Google Scholar
26 Brousset P, Sabatier J, Galateau-Salle F. SV40 infection in human cancers. Ann Oncol 2005; 16: 1212– 13.
Crossref CAS PubMed Web of Science®Google Scholar
27 Aoe K, Hiraki A, Murakami T, Toyooka S, Shivapurkar N, Gazdar AF, Sueoka N, Taguchi K, Kamei T, Takeyama H, Sugi K, Kishimoto T. Infrequent existence of simian virus 40 large T antigen DNA in malignant mesothelioma in Japan. Cancer Sci 2006; 97: 292– 5.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
28 DeRienzo A, Tor M, Sterman DH, Aksoy F, Albelda SM, Testa JR. Detection of SV40 DNA sequences in malignant mesothelioma specimens from the United States, but not from Turkey. J Cell Biochem 2002; 84: 455– 9.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
29 Priftakis P, Bogdanovic G, Hjerpe A, Dalianis T. Presence of simian virus 40 (SV40) is not frequent in Swedish malignant mesotheliomas. Anticancer Res 2002; 22: 1357– 60.
PubMed Web of Science®Google Scholar
30 Cristaudo A, Foddis R, Vivaldi A, Buselli R, Gattini V, Guglielmi G, Cossentino F, Ottenga F, Ciancia E, Libener R, Filiberti R, Neri M, et al. SV40 enhances the risk of malignant mesothelioma among people exposed to asbestos: a molecular epidemiologic case-control study. Cancer Res 2005; 65: 3049– 52.
Crossref CAS PubMed Web of Science®Google Scholar
31 Kim JY, Koralnik IJ, LeFave M, Segal RA, Pfister LA, Pomeroy SL. Medulloblastomas and primitive neuroectodermal tumors rarely contain polyomavirus DNA sequences. Neuro-oncology 2002; 4: 165– 70.
Crossref PubMed Web of Science®Google Scholar
32 Engels EA, Sarkar C, Daniel RW, Gravitt PE, Verma K, Quezado M, Shah KV. Absence of simian virus 40 in human brain tumors from northern India. Int J Cancer 2002; 101: 348– 52.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
33 Montesinos-Rongen M, Besleaga R, Heinsohn S, Siebert R, Kabisch H, Wiestler OD, Deckert M. Absence of simian virus 40 DNA sequences in primary central nervous system lymphoma in HIV-negative patients. Virchows Arch 2004; 444: 436– 8.
Crossref PubMed Web of Science®Google Scholar
34 Rollison DEM, Utaipat U, Ryschkewitsch C, Hou J, Goldthwaite P, Daniel R, Helzlsouer KJ, Burger PC, Shah KV, Major EO. An investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories. Int J Cancer 2005; 113: 769– 74.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
35 Sabatier J, Uro-Coste E, Benouaich A, Boetto S, Gigaud M, Tremoulet M, Delisle MB, Galateau-Salle F, Brousset P. Immunodetection of SV40 large T antigen in human central nervous system tumours. J Clin Pathol 2005; 58: 429– 31.
Crossref CAS PubMed Web of Science®Google Scholar
36 Martini F, Lazzarin L, Iaccheri L, Vignocchi B, Finocchiaro G, Magnani I, Serra M, Scotlandi K, Barbanti-Brodano G, Tognon M. Different simian virus 40 genomic regions and sequences homologous with SV40 large T antigen in DNA of human brain and bone tumors and of leukocytes from blood donors. Cancer 2002; 94: 1037– 48.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
37 Capello D, Rossi D, Gaudino G, Carbone A, Gaidano G. Simian virus 40 infection in lymphoproliferative disorders. Lancet 2003; 361: 88– 9.
Crossref PubMed Web of Science®Google Scholar
38 MacKenzie J, Wilson KS, Perry J, Gallagher A, Jarrett RF. Association between simian virus 40 DNA and lymphoma in the United Kingdom. J Natl Cancer Inst 2003; 95: 1001– 3.
Crossref CAS PubMed Web of Science®Google Scholar
39 Daibata M, Nemoto Y, Kamioka M, Imai S, Taguchi H. Simian virus 40 in Japanese patients with lymphoproliferative disorders. Br J Haematol 2003; 121: 190– 1.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
40 Brousset P, deAraujo V, Gascoyne RD. Immunohistochemical investigation of SV40 large T antigen in Hodgkin and non-Hodgkin's lymphoma. Int J Cancer 2004; 112: 533– 5.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
41 Sui LF, Williamson J, Lowenthal RM, Parker AJ. Absence of simian virus 40 (SV40) DNA in lymphoma samples from Tasmania, Australia. Pathology 2005; 37: 157– 9.
Crossref CAS PubMed Web of Science®Google Scholar
42 Schuler F, Dolken SC, Hirt C, Dolken MT, Mentel R, Gurtler LG, Dolken G. No evidence for simian virus 40 DNA sequences in malignant non-Hodgkin lymphomas. Int J Cancer 2006; 118: 498– 504.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
43 Vilchez RA, Madden CR, Kozinetz CA, Halvorson SJ, White ZS, Jorgensen JL, Finch CJ, Butel JS. Association between simian virus 40 and non-Hodgkin lymphoma. Lancet 2002; 359: 817– 23.
Crossref CAS PubMed Web of Science®Google Scholar
44 Shivapurkar N, Harada K, Reddy J, Scheuermann RH, Xu Y, McKenna RW, Milchgrub S, Kroft SH, Feng Z, Gazdar AF. Presence of simian virus 40 DNA sequences in human lymphomas. Lancet 2002; 359: 851– 2.
Crossref CAS PubMed Web of Science®Google Scholar
45 Nakatsuka S, Liu A, Dong Z, Nomura S, Takakuwa T, Miyazato H, Aozasa K. Simian virus 40 sequences in malignant lymphomas in Japan. Cancer Res 2003; 63: 7606– 8.
CAS PubMed Web of Science®Google Scholar
46 Shivapurkar N, Takahashi T, Reddy J, Zheng Y, Stastny V, Collins R, Toyooka S, Suzuki M, Parikh G, Asplund S, Kroft SH, Timmons C, et al. Presence of simian virus 40 DNA sequences in human lymphoid and hematopoietic malignancies and their relationship to aberrant promoter methylation of multiple genes. Cancer Res 2004; 64: 3757– 60.
Crossref CAS PubMed Web of Science®Google Scholar
47 Meneses A, Lopez-Terrada D, Zanwar P, Killen DE, Monterroso V, Butel JS, Vilchez RA. Lymphoproliferative disorders in Costa Rica and simian virus 40. Haematologica 2005; 90: 1635– 42.
PubMed Web of Science®Google Scholar
48 Carbone M, Pass HI, Rizzo P, Marinetti M, Di Muzio M, Mew DJY, Levine AS, Procopio A. Simian virus 40-like sequences in human pleural mesothelioma. Oncogene 1994; 9: 1781– 90.
CAS PubMed Web of Science®Google Scholar
49 Galateau-Salle F, Iwatsubo Y, Gennetay E, Renier A, Letourneux M, Pairon JC, Moritz S, Brochard P, Jaurand MD, Freymuth F. SV40-like DNA sequences in pleural mesothelioma, bronchopulmonary carcinoma, and non-malignant pulmonary diseases. J Pathol 1998; 184: 252– 7.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
50 Volter C, zur Hausen H, Alber D, de Villiers EM. A broad spectrum PCR method for the detection of polyomaviruses and avoidance of contamination by cloning vectors. Dev Biol Stand 1998; 94: 137– 42.
CAS PubMed Web of Science®Google Scholar
51 Griffiths DJ, Nicholson AG, Weiss RA. Detection of SV40 sequences in human mesothelioma. Dev Biol Stand 1998; 94: 127– 36.
CAS PubMed Web of Science®Google Scholar
52 Bergsagel DJ, Finegold MJ, Butel JS, Kupsky WJ, Garcea RL. DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood. N Engl J Med 1992; 326: 988– 93.
Crossref CAS PubMed Web of Science®Google Scholar
53 Martini F, Iaccheri L, Lazzarin L, Carinci P, Corallini A, Gerosa M, Iuzzolino P, Barbanti-Brodano G, Tognon M. 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.
CAS PubMed Web of Science®Google Scholar
54 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– 44.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
55 Arrington AS, Moore MS, Butel JS. SV40-positive brain tumor in scientist with risk of laboratory exposure to the virus. Oncogene 2004; 23: 2231– 5.
Crossref CAS PubMed Web of Science®Google Scholar
56 Yazdi AS, Puchta U, Flaig MJ, Sander CA. Lack of evidence for the presence of Simian virus 40 DNA in cutaneous lymphomas. J Invest Dermatol 2003; 121: 212– 13.
Crossref PubMed Web of Science®Google Scholar
57 Ozdarendeli A, Camci C, Aygen E, Kirkil C, Toroman ZA, Dogru O, Doymaz MZ. SV40 in human thyroid nodules. J Clin Virol 2004; 30: 337– 40.
Crossref CAS PubMed Web of Science®Google Scholar
58 Wong NA, Rae F, Herriot MM, Mayer NJ, Brewster DH, Harrison DJ. SV40 tag DNA sequences, present in a small proportion of human hepatocellular carcinomas, are associated with reduced survival. J Clin Pathol 2003; 56: 904– 9.
Crossref CAS PubMed Web of Science®Google Scholar
59 Martini F, Iaccheri L, Martinelli M, Martinello R, Grandi E, Mollica G, Tognon M. Papilloma and polyoma DNA tumor virus sequences in female genital tumors. Cancer Invest 2004; 22: 697– 705.
Crossref CAS PubMed Web of Science®Google Scholar
60 Li RM, Branton MH, Tanawattanacharoen S, Falk RA, Jennette JC, Kopp JB. Molecular identification of SV40 infection in human subjects and possible association with kidney disease. J Am Soc Nephrol 2002; 13: 2320– 30.
Crossref CAS PubMed Web of Science®Google Scholar
61 Li RM, Mannon RB, Kleiner D, Tsokos M, Bynum M, Kirk AD, Kopp JB. BK virus and SV40 co-infection in polyomavirus nephropathy. Transplantation 2002; 74: 1497– 1504.
Crossref PubMed Web of Science®Google Scholar
62 Shah KV, Daniel RW, Strickler HD, Goedert JJ. Investigation of human urine for genomic sequences of the primate polyomaviruses simian virus 40, BK virus, and JC virus. J Infect Dis 1997; 176: 1618– 21.
Crossref CAS PubMed Web of Science®Google Scholar
63 Galdenzi G, Lupo A, Anglani F, Perini M, Galeazzi L, Giunta S, Marcantoni C, Del Prete D, Graziatto R, D'Angelo A, Maschio G, Gambaro G. Is the simian virus SV40 associated with idiopathic focal segmental glomerulosclerosis in humans? J Nephrol 2003; 16: 350– 6.
CAS PubMed Web of Science®Google Scholar
64 International SV40 Working Group. A multicenter evaluation of assays for detection of SV40 DNA and results in masked mesothelioma specimens. Cancer Epidemiol Biomarkers Prev 2001; 10: 523– 32.
PubMed Web of Science®Google Scholar
65 Shah KV, Galloway DA, Knowles WA, Viscidi RP. Simian virus 40 (SV40) and human cancer: a review of the serological data. Rev Med Virol 2004; 14: 1– 9.
Wiley Online Library PubMed Web of Science®Google Scholar
66 Viscidi RP, Rollison DE, Viscidi E, Clayman B, Rubalcaba E, Daniel R, Major EO, Shah KV. Serological cross-reactivities between antibodies to simian virus 40, BK virus, and JC virus assessed by virus-like-particle-based enzyme immunoassays. Clin Diagn Lab Immunol 2003; 10: 278– 85.
Crossref CAS PubMed Web of Science®Google Scholar
67 Viscidi RP, Clayman B. Serological cross reactivity between polyomavirus capsids. In: N Ahsan, ed. Polyomaviruses and human diseases. Georgetown, TX: Landes Bioscience, 2006; 73– 84.
Crossref Web of Science®Google Scholar
68 Knowles WA, Pipkin P, Andrews N, Vyse A, Minor P, Brown DWG, Miller E. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 2003; 71: 115– 23.
Wiley Online Library PubMed Web of Science®Google Scholar
69 Carter JJ, Madeleine MM, Wipf GC, Garcea RL, Pipkin PA, Minor PD, Galloway DA. Lack of serological evidence for prevalent SV40 infection in humans. J Natl Cancer Inst 2003; 95: 1522– 30.
Crossref PubMed Web of Science®Google Scholar
70 Sanjose S, Shah KV, Domingo-Domenech E, Engels EA, Sevilla AF, Alvaro T, Garcia-Villanueva M, Romagosa V, Gonzalez-Barca E, Viscidi RP. Lack of serological evidence for an association between simian virus 40 and lymphoma. Int J Cancer 2003; 104: 522– 4.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
71 Strickler HD, Goedert JJ, Fleming M, Travis WD, Williams AE, Rabkin CS, Daniel RW, Shah KV. Simian virus 40 and pleural mesothelioma in humans. Cancer Epidemiol Biomarkers Prev 1996; 5: 473– 5.
CAS PubMed Web of Science®Google Scholar
72 Rollison DE, Helzlsouer KJ, Alberg AJ, Hoffman S, Hou J, Daniel R, Shah KV, Major EO. Serum antibodies to JC virus, BK virus, simian virus 40, and the risk of incident adult astrocytic brain tumors. Cancer Epidemiol Biomarkers Prev 2003; 12: 460– 3.
PubMed Web of Science®Google Scholar
73 Rollison DE, Helzlsouer KJ, Halsey NA, Shah KV, Viscidi RP. Markers of past infection with simian virus 40 (SV40) and risk of incident non-Hodgkin lymphoma in a Maryland cohort. Cancer Epidemiol Biomarkers Prev 2005; 14: 1448– 52.
Crossref PubMed Web of Science®Google Scholar
74 Engels EA, Viscidi RP, Galloway DA, Carter JJ, Cerhan JR, Davis S, Cozen W, Severson RK, Sanjose S, Colt JH, Hartge P. Case-control study of simian virus 40 and non-Hodgkin lymphoma in the United States. J Natl Cancer Inst 2004; 96: 1368– 74.
Crossref PubMed Web of Science®Google Scholar
75 Engels EA, Chen J, Hartge P, Cerhan JR, Davis S, Severson RK, Cozen W, Viscidi RP. Antibody responses to simian virus 40 T antigen: a case-control study of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 2005; 14: 521– 4.
Crossref CAS PubMed Web of Science®Google Scholar
76 Shah KV, Daniel RW, Murphy G. Antibodies reacting to Simian virus 40 T antigen in human sera. J Natl Cancer Inst 1973; 51: 687– 90.
CAS PubMed Web of Science®Google Scholar
77 Rollison DE, Page WF, Crawford H, Gridley G, Wacholder S, Martin J, Miller R, Engels EA. Case-control study of cancer among US Army veterans exposed to simian virus 40-contaminated adenovirus vaccine. Am J Epidemiol 2004; 160: 317– 24.
Crossref PubMed Web of Science®Google Scholar
78 Engels EA, Katki HA, Nielsen NM, Winther JF, Hjalgrim H, Gjerris F, Rosenberg PS, Frisch M. Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40. J Natl Cancer Inst 2003; 95: 532– 9.
Crossref CAS PubMed Web of Science®Google Scholar
79 Strickler HD, Goedert JJ, Devesa SS, Lahey J, Fraumeni JF,Jr, Rosenberg PS. Trends in U.S. pleural mesothelioma incidence rates following simian virus 40 contamination of early poliovirus vaccines. J Natl Cancer Inst 2003; 95: 38– 45.
Crossref CAS PubMed Web of Science®Google Scholar
80 Thu GO, Hem LY, Hansen S, Moller B, Norstein J, Nokleby H, Grotmol T. Is there an association between SV40 contaminated polio vaccine and lymphoproliferative disorders? An age-period-cohort analysis on Norwegian data from 1953 to 1997. Int J Cancer 2006; 118: 2035– 9.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
81 Fisher SG, Weber L, Carbone M. Cancer risk associated with simian virus 40 contaminated polio vaccine. Anticancer Res 1999; 19: 2173– 80.
CAS PubMed Web of Science®Google Scholar

Citing Literature

Volume120, Issue2

15 January 2007

Pages 215-223

SV40 and human cancer: A review of recent data

Abstract

Background