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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2012  |  Volume : 23  |  Issue : 1  |  Page : 53-57
Role of viruses in renal cell carcinoma

1 Department of Urology, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Urology; Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
3 School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
4 Organ Transplant Research Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

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Date of Web Publication3-Jan-2012


To determine whether viral infections are related to renal cell carcinoma (RCC), we studied 49 patients with RCC (29 patients were males with age ranging from 30 to 81 years and a mean of 57.5 years; 20 patients were females with age ranging from 36 to 70 years with a mean of 58.4 years) and 16 non-neoplastic kidney patients as controls. Tissues specimens from study patients and controls were examined by nested polymerase chain reaction (PCR) to determine the presence of DNA of several viruses including human papilloma virus (HPV), Epstein-Barr virus (EBV), and polyoma viruses (BKV and JCV). Our results revealed that 7 of 49 (14.29%) RCC tissue specimens had HPV DNA compared with none of 16 non-cancer control subjects. Regarding the HPV types, all the positive results were high-risk HPV types (type 16 in three and 18 in four patients). The present study suggests that HPV infection, especially high-risk types, is associated with RCC. However, more studies are necessary to demonstrate the molecular oncogenic processes involved in this association.

How to cite this article:
Salehipoor M, Khezri A, Behzad-Behbahani A, Geramizadeh B, Rahsaz M, Aghdaei M, Afrasiabi MA. Role of viruses in renal cell carcinoma. Saudi J Kidney Dis Transpl 2012;23:53-7

How to cite this URL:
Salehipoor M, Khezri A, Behzad-Behbahani A, Geramizadeh B, Rahsaz M, Aghdaei M, Afrasiabi MA. Role of viruses in renal cell carcinoma. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2022 Sep 28];23:53-7. Available from: https://www.sjkdt.org/text.asp?2012/23/1/53/91301

   Introduction Top

Renal cell carcinoma (RCC) is the most common malignant disease of the adult kidney. [1] The incidence of RCC has been increasing globally. [2],[3] In the United States, 51,200 new cases and 13,000 deaths were reported in 2007. [4] Obesity, smoking, and hypertension are the known risk factors for RCC. [5],[6],[7],[8],[9],[10],[11] Taken together, these risk factors account for 49% of cases of RCC; [12] thus, a large proportion of them remains unexplained and the search for additional risk factors should continue. In the past 25 years, revelations on the genesis of human cancer have come at an increasing pace. Infectious agents, especially viruses, account for several of the most common malignancies - up to 20% of all cancers. [13]

In this study, we aimed to determine the presence of viruses in the cancer tissue specimens submitted for diagnosis of the RCC by screening for the commonly known viruses.

   Materials and Methods Top

We studied 49 patients with clinical and histopathologic diagnosis of RCC at the Department of Urology, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran, from 2003 to 2006, in addition to 16 patients who underwent nephrectomy due to trauma as controls. Paraffin blocks of tissue specimens were examined in the Department of Pathology, Shiraz University of Medical Sciences. Five-micrometer-thick sections were cut and collected in sterile tubes. To avoid contamination between various specimens, special care was taken. The knife was cleaned up before cutting each new tissue sample. The specimen holder of the microtome was washed several times with absolute alcohol between cuttings.

DNA extraction and virus detection

Formalin-fixed paraffin-embedded tissues were processed with "QIAamp Tissue Kit" according to the manufacturer's instructions (Quiagene, Hilden, Germany); "QIAamp" total DNA purification comprises cellular lysis, proteinase K digestion, adsorption of the lysate to the cell lysate to the OIAamp silica membrane, and washing steps and elution of the membrane-bound DNA. Negative controls were processed with "QIAamp Tissue kit" as described above.

We used 10 μL of purified total cellular DNA for human papilloma virus (HPV) nested polymerase chain reaction (PCR) utilizing consensus primers, MY/GP, for genome detection of a broad spectrum of HPV geno-types according to the method of Soltar et al. [14]

To determine the specific type of HPV, PCR products were purified with a gel extraction kit (Qiagen) and sequenced by the dye-deoxy terminator method on a 377 ABI Prism Sequencer (PE Applied Biosystems) using sequencing of an L 1 major capsid.

The data were analyzed using BIOEDIT/ BLASTN package. PCR was also employed for determination of polyoma virus (BKV and JCV) DNA and for Epstein-Barr virus (EBV) DNA in extracted DNA, respectively. The 20-base oligonucleotide primers, PEP-1 and PEP-2, specific for sequence within the large-T and small t region of the both BKV and JCV genome, were used. [15] PCR amplification was performed according to the method of Behzad-Behbahani et al. [16] The lengths of the BKV and JCV genomes targeted for amplification were 176 and 173 bp, respectively. Digestion of the PCR products with BamHI prior to electrophoresis was used to discriminate between BKV and JCV sequences. The JCV sequence targeted for amplification contained a BamHI site, whereas the BKV sequence was not cleaved. The JCV DNA was cleaved into fragments of 120 and 23 bp by BamHI. The threshold of sensitivity of the PCR was determined using 10-fold serial dilution of the plasmid DNA.

Furthermore, the EBV-PCR was used to study DNA extracted from the formalin-fixed paraffin-embedded RCC tissues. The primers were directed to the conserved region of the EBV genome encoding capsid protein gp220. The length of the amplicon was 277 bp. [17]

DNA extracted from infected LCL-P17 cell line, i.e. human EBV transformed peripheral blood B-cells, was used as the positive control for EBV-PCR. Each PCR processing procedure was performed in a physically separate room to prevent contamination. Negative controls were used to ensure that carryover contamination would not occur. To exclude false-negative results, amplification of the human β-globin gene was performed by using published primer sequences to assess the adequacy of each specimen. [18]

Detection of PCR product

Ten μl of reaction product was electrophoresed in 1.5% agarose gel made in Tris-acetated-ethylenediaminetetraacetic acid (EDTA) (TAE) buffer (pH = 8.0-8.5) and visualized by UV illumination after ethidium bromide (10 μ/mL) staining. Positive and negative controls were also treated as samples. The sensitivities of PCR assays for detection of HPV-DNA, polyomavirus DNA, and EBV-DNA in clinical specimens were found to be 300 copies/mL, 900 copies/mL, and 800 copies/mL of each genome, respectively.

   Statistical Analysis Top

The data were analyzed using SPSS statistical software, version 11.5.0.

   Results Top

A total of 65 individuals, including 49 RCCs and 16 non-cancer controls, were recruited into this study.

In the study group, there were 29 male patients, with age ranging from 30 to 81 years and a mean of 57.5 years, and 20 female patients, with age ranging from 36 to 70 years and a mean age of 58.4 years. On the other hand, the control group included 11 male patients, with age ranging from 20 to 45 years and a mean of 33.09 years, and five female patients, with age ranging from 22 to 40 years and a mean of 30.6 years.

HPV by nested PCR was detected in seven of 49 (14.29%) RCC tissues, but in none of the 16 controls. Regarding the HPV types, all the positive results were high-risk HPV types (type 16 in three and type18 in four patients; 3 and 57%, respectively) [Table 1].
Table 1: The characteristics of the study patients with positive viral infected renal cell carcinoma tissue specimens.

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   Discussion Top

The first consistent observations that viruses could be associated with some types of cancer were made almost a century ago. Since then, several studies have been carried out with this aim. As a result of these studies, a strong link between some viral agents and several human cancers has been found. Infection by viruses accounts for almost 15% of all human malignancies. [19]

HPV are consistently associated with cancer of the cervix. However, only some types of HPV regularly have this relation. Of the approximately 130 HPV types distinguished so far, 30 are so-called anogenital types. More recently, the virus has been associated with up to 20% of cancers of the oropharynx, especially tonsillar; the latest emerging association is with basal cell and squamous-cell carcinomas of the skin. [20] EBV, a member of the human herpes virus family, establishes a lifelong latent infection within the memory B lymphocytes after primary infection. Like all herpes viruses, EBV has been detected in a variety of lymphoid, epithelial, and even mesenchymal tumors. [21] There are three primate polyoma viruses: JCV, BKV, and SV40, and there is evidence of their role in developing neoplasia. [22],[23]

JCV, a human virus that infects the brain and the kidney, is able to transform cells in culture although not as efficiently as SV40. JVC has high oncogenicity in animals. The virus induces multiple types of brain tumors when injected into the brains of newborn Golden Syrian hamsters. JCV is the only polyoma virus that induces solid tumors in nonhuman primates. [23],[24]

BKV is a human virus that infects lymphocytes and cells in the urogenital tract in vivo. BKV is highly oncogenic in young or newborn mice, rats, and hamsters. The types of tumors induced include ependymoma, neuroblastoma, pineal gland tumors, pancreatic islet cell tumors, fibrosarcoma, and osteosarcoma, which suggests a tropism of the virus for certain cell types. [25]

There have been few studies regarding the viral etiology of RCC. Kwang Hee Kim et al found that EBV infection is related to sarcomatoid RCC tissues. [26] Shimakage et al suggested that the expression of EBV may be involved in the pathogenesis of RCC. [27]

The association between HPV and RCC has not been studied. HPV is thought to be the most frequently acquired sexually transmitted viral infection worldwide. Its annual incidence was estimated to be about six million cases in the United States. HPV association with the development of penile lesions, such as condyloma acuminatum, verrucous carcinoma, and squamous cell carcinomas, was recognized. John S. Wiener et al reported the association between HPV type 16 and squamous cell carcinoma of male urethra. [28] Furthermore, HPV seem to be responsible for more than 95% of cervical cancers in women. Preliminary reports have also shown its association with subsequent development of bladder and prostate cancers. Other than genitourinary tract, its copresentation was observed in anal, head and neck squamous cell carcinomas. Although most of these infections are transient, many of HPV-related cancers present decades later.

HPV types 6, 11, 42, 44, 53-55, and 66 have been associated with the development of benign neoplasms. Viral types 16, 18, 31, 33, 39, 45, 52, 56, and 58 are seen with squamous cell malignancies and precancerous lesions and are considered as high risks. In our study, RCC association with types 16 and 18 of HPV was found.

We conclude that the present study suggests strong association of HPV, especially high-risk types, with RCC. Our study was limited by the small number of patients in the case and control groups, limiting its statistical power. Additional studies with larger number of patients are warranted to confirm our results.

   Acknowledgment Top

This work was financially supported by a grant from Shiraz Institute for Cancer Research (Grant Number ICR-84-113).

   References Top

1.Sokoloff MH, deKernion JB, Figlin RA, et al: Current management of renal cell carcinoma. CA Cancer J Clin 1996;46:284-302.  Back to cited text no. 1
2.Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States. JAMA 1999;281:1628-31.  Back to cited text no. 2
3.Mathew A, Devesa SS, Fraumeni JF Jr, et al. Global increases in kidney cancer incidence, 1973-1992. Eur J Cancer Prev 2002;11:171-8.  Back to cited text no. 3
4.American Cancer Society. Cancer facts & figures 2007. Atlanta, GA: American Cancer Society, 2007.  Back to cited text no. 4
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18.Saiki PK, Gelfand DH, Stoffel S, et al. Primerdircted enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:486-91.  Back to cited text no. 18
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21.Murray PG, Young LS. Epstein-Barr virus infection: basis of malignancy and potential for therapy. Expert Rev Mol Med 2001;15:1-20.  Back to cited text no. 21
22.White MK, Khalili K. Signaling pathways and polyomavirus oncoproteins: importance in malignant transformation. Gene Ther Mol Biol 2004;8:19-30.  Back to cited text no. 22
23.Khalili K, Del Valle L, Otte J, Weaver M, Gordon J. Human neurotropic polyomavirus, JCV, and its role in carcinogenesis. Oncogene 2003;22:5181-91.  Back to cited text no. 23
24.Del Valle L, Gordon J, Ferrante P, Khalili K. JC virus in experimental and clinical brain tumorigenesis. In: Khalili K, Stoner GL, eds. Human polyomaviruses: molecular and clinical perspectives. New York: Wiley-Liss Inc.; 2001;409-30.  Back to cited text no. 24
25.Corallini A, Tognon M, Negrini M, Barbanti-Brodano G. Evidence for BK virus as a human tumor virus. In: Khalili K, Stoner GL, eds. Human polyomaviruses: molecular and clinical perspectives. Wiley-Liss Inc., New York; 2001;431-60.  Back to cited text no. 25
26.Kim KH, Han EM, Lee ES, Park HS, Kim I, Kim YS. Epstein-Barr virus infection in sarco-matoid renal cell carcinoma tissues. BJU Int 2005;96(4):547-52.  Back to cited text no. 26
27.Shimakage M, Kawahara K, Harada S, Sasagawa T, Shinka T, Oka T. Expression of Epstein-Barr virus in renal cell carcinoma. Oncol Rep 2007;18(1):41-6  Back to cited text no. 27
28.Wiener JS, Liu ET, Walther PJ. Oncogenic human papillomavirus type 16 is associated with squamous cell cancer of the male urethra. Cancer Res 1992;52(18):5018-23.  Back to cited text no. 28

Correspondence Address:
Mohammad Amin Afrasiabi
Department of Urology, Faghihi Hospital, Shiraz University of Medical Sciences, P.O. Box 71345-51154, Shiraz
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Source of Support: None, Conflict of Interest: None

PMID: 22237219

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