© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 13, 1166,
July 7, 1999
© 1999 Oxford University Press
CORRESPONDENCE |
Re: Cell and Molecular Biology of Simian Virus 40: Implications for Human Infections and Disease
Affiliations of authors: B. G. M. Durie, Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA; H. B. Urnovitz, Chronic Illness Research Foundation, Berkeley, CA.
Correspondence to: Brian G. M. Durie, M.D., Cedars-Sinai Comprehensive Cancer Center, Clinical Research and Myeloma Programs, Division of Hematology/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048.
Increasing data support the notion that simian virus 40 (SV40) is
involved in the pathogenesis of several human malignancies
(1,2). The exact etiopathology of SV40 and cancer is still a
mystery. One approach for unraveling the connection between viral
exposures and cancer is to recognize the molecular mechanisms of
cellular responses to toxic exposures. Several concepts have to be
considered in these multifactorial disease processes. The first concept
is the mechanism whereby B lymphocytes respond to toxic challenge.
Antibody-producing B lymphocytes do not store genes for each possible
toxin. Instead, the genome has hot spots of antigen-responsive
multigene families that can generate the necessary protein diversity
for detoxifying unpredictable agents. The diversity is generated
at the level of DNA somatic rearrangements and RNA splicing. This
genetic material is rearranged, selected, and reinserted back into the
genome. One hot spot from which these rearrangements occur is found on
chromosome 22q11.2, where the immunoglobulin 
light chain region
is located. This region is also an active site linked to
SV40-associated malignancies, including mesotheliomas, meningiomas,
sarcomas, ependymomas, and neuroectodermal tumors.
The second concept is the role of retroelements in chronic illnesses (3). Approximately 1% of the human genome is endogenous retroviruses, and another 5% of the genome are short, interspersed, nuclear retroelements known as Alu sequences. Alu retroelements are important because of the following: 1) they are expressed as a result of viral infection, cell stress, and toxic exposures; 2) they are actively involved in recombinatorial events leading to novel RNA generation; and 3) they are inextricably linked to primate evolution. SV40 T-antigen recognizes binding sites present within Alu family sequences (4).
The third concept is the detection of RNA in serum and plasma. Novel "rearranged" RNA, with chromosome 22q11.2 segments, has been detected in the serum of veterans who have Persian Gulf War-related illnesses (5). The presence of plasma RNA also has been described for several cancers (6). In studying active human multiple myeloma, we have noted the presence of an unique plasma RNA species (GenBank accession number AFO18254) that has 99% homology from four different patients (7). Sequencing of the amplicon from reverse transcription-polymerase chain reaction revealed a 713-nucleotide segment from the flanking region of the PPAR gene (GenBank accession number HSBSE3A) at chromosome 22q11.2. Interestingly, the PPAR gene is specifically triggered by pesticides and herbicides. Within the segment was an Alu retroelement containing two SV40 T-antigen binding sites.
Appreciating the concepts outlined above will further assist us in dissecting the molecular pathways by which cells respond to genotoxic events. Finding fingerprints of viruses (e.g., SV40) is just as meaningful as finding the entire viral genome for determining the factors leading to tumorigenesis. New techniques and procedures are needed to identify and measure the cumulative damage to the genome, cell, and body to fully understand the associations between SV40 and cancer.
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.cancerlit;99120728
2 Carbone M, Rizzo P, Pass HI. Simian virus 40, poliovaccines and human tumors: a review of recent developments. Oncogene 1997;15:1877-88.[CrossRef][Web of Science][Medline]cancerlit;98030515
3 Urnovitz HB, Murphy WH. Human endogenous retroviruses: nature, occurrence, and clinical implications in human disease. Clin Microbiol Rev1996 ;9:72-99.[Abstract]
4
Darlix JL, Khandjian EW, Weil R. Nature and origin of the RNA
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5
Urnovitz HB, Tuite JJ, Higashida JM, Murphy WH. RNA in the
sera of persian gulf war veterans have segments homologous to chromosome 22q11.2. Clin Diagn Lab Immunol 1999;6:330-5.
6
Wieczorek AJ, Rhyner C, Block LH. Isolation and
characterization of an RNA-proteolipid complex associated with the malignant state in humans.Proc Natl Acad Sci U S A
1985;82;3455-9.
7 Durie BG, Villarete L, Arvard A, Ornopia M, Urnovitz HB. Nucleic acid sequence in plasma of human myeloma contains critical breakpoint region with an Alu insert incorporating two SV40 T-antigen binding sites. Blood 1997;90:1070.
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