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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 52  |  Issue : 1  |  Page : 42-45
The absence of JC virus antigens in Indian children with medulloblastomas


1 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 011, UT, India
2 Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 011, UT, India
3 Department of Neurology, Johns Hopkins Institute, Maryland, USA

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   Abstract 

Background: The human polyoma virus, also known as the JC virus (JCV), replicates predominantly in the oligodendrocytes, the myelin producing cells in the central nervous system and results in the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) especially in immunosuppressed patients with AIDS. Several investigators have also documented the presence of the viral genome and early and late antigens in a variety of brain tumors particularly in medulloblastomas, gliomas and ependymomas. Reports also indicate the presence of JCV in patients with colon cancer. The T antigen of JCV has been postulated to have oncogenic potential as substantiated by animal experiments. Although JCV infects 80% of the population, there are scant epidemiological studies regarding JCV from India. There are also reports of the low prevalence of PML in patients with AIDS from India and Africa. Aim: This study was undertaken to investigate if Indian children with medulloblastomas also show evidence of JCV. Methods: Twenty-two consecutive cases of medulloblastomas were investigated for the presence of T antigen and agnoprotein of JCV in biopsy specimens by immunohistochemistry. Antibodies to the agnoprotein antigen raised in rabbits and a monoclonal antibody against SV40 T antigen raised in mice that cross-reacts with JCV T antigen were used. Results: Out of 22 patients, 4 had desmoplastic tumors while the rest had classical tumors. All children were below the age of 10. Results indicate that while PML tissues showed consistent immunostaining both with antibody to T antigen and agnoprotein antibody, none of the tumors showed any positive staining for JC viral antigens. Conclusion: JCV antigens could not be detected by immunohistochemistry in the tumor tissues of Indian children with medulloblastomas.

Keywords: Human polyoma virus, JC virus, progressive multifocal leukoencephalopathy, India, Children, Medulloblastoma

How to cite this article:
Vasishta RK, Pasricha N, Nath A, Sehgal S. The absence of JC virus antigens in Indian children with medulloblastomas. Indian J Pathol Microbiol 2009;52:42-5

How to cite this URL:
Vasishta RK, Pasricha N, Nath A, Sehgal S. The absence of JC virus antigens in Indian children with medulloblastomas. Indian J Pathol Microbiol [serial online] 2009 [cited 2019 Dec 12];52:42-5. Available from: http://www.ijpmonline.org/text.asp?2009/52/1/42/44961



   Introduction Top


JC virus infection has kindled added interest in the wake of acquired immune deficiency syndrome (AIDS) associated progressive multifocal leucoencephalopathy (PML). [1],[2],[3] The virus infects, primarily, the oligodendrocytes resulting in demyelination. The expression of one of the early gene products, T antigen, is proposed to be vital for the initiation of a lytic cycle, stimulation of DNA replication and expression of late genes e.g., agnoprotein. [4] Several in vivo models have documented the capacity of T antigen to induce neural tumors. Intracerebral inoculation of the JC virus induces medulloblastomas, astrocytomas and glioblastomas. [5],[6],[7] These viruses induce distinct tissue specific tumors.[8] Nagasaki, et al. [9] from Japan also documented the induction of brain tumors with the JC virus. It is postulated that T antigen interacts with several tumor suppressor genes and inactivates them. [10],[11] In a recent study, Del Valle, et al. [12] showed wide spread localization of agnoprotein in the neoplastic cells of medulloblastomas. In their study, the T antigen was present in some but not all the tumors positive for agnoprotein. The authors concluded that the findings of agnoprotein in the absence of T antigen in some tumors point towards the potential role of agnoprotein in the pathogenesis of medulloblastomas associated with the JC virus. On the other hand, some authors have questioned the role of the JC virus in these tumors despite the presence of p53 protein in anaplastic tumor cells. [13]

In India, PML has only rarely been documented in patients with AIDS, [14] the most common opportunistic infections being fungal or bacterial. [15]

This study is aimed to assess if Indian children with medulloblastomas also show evidence of JC virus infection. If not, it would point towards additional, hitherto unrecognized causative agents.


   Materials and Methods Top


Cases of medulloblastomas were collected from the Department of Histopathology attached to Nehru Hospital, PGIMER, Chandigarh. The tumors were categorized according to the World Health Organization's (WHO) system of classification [16] noting special features and designated as classical, desmoplastic, desmoplastic with extensive nodularity, anaplastic and large cell medulloblastoma.

Sections of 5 micron thickness in duplicate were stained for agnoprotein and T antigen of SV40 each according to the method Advocated by Del Valle et al [20] with minor modifications. Antigen retrieval was done on deparafinized sections by heating in 0.01 molar citrate buffer (pH6.00) in a microwave oven for 3 cycles of 10 minutes each. The sections were washed in several changes of phosphate buffer saline and endogenous peroxidase blocked with methanol in 3% hydrogen peroxide solution. The primary antibodies were kindly gifted by Dr. Khalili (Temple University, PA, U.S.A.). The polyclonal rabbit anti agnoprotein antibody was diluted 1 in 2000 while the mouse monoclonal anti SV40 T antibody (cross reacting with JCV T antigen) was diluted 1 in 200. The avidin biotin detection system for mouse and rabbit were purchased from Dakopatts, Sweden. The subsequent steps were performed according to the manufacturer's instructions. The reaction was finally developed with 0.05% diaminobenzidine (DAB) (3,3-diaminobenzidine, Serva, Heidelberg, Germany) solution in phosphate buffer saline (PBS) containing 0.015% H2O2. Slides were lightly counterstained with Mayer's hematoxyline and mounted in DPX. Multiple sections from a patient with PML were used as positive controls with each batch of staining. Normal human brain sections were used as negative controls.


   Results Top


A total of 22 patients with medulloblastomas were studied and all were below 10 years of age. A majority of the tumors were of the classical type and only 4 out of 22 patients had desmoplastic medulloblastomas. None of the patients had anaplastic tumors. On immunohistochemistry, tissue sections from patients with PML showed demyelination, patchy bizarre nuclear changes in astrocytes and oligodendrrocytes, giant oligodendrocytes and strong staining reaction with anti agnoprotein antibodies as well as with anti T antigen antibodies [Figure 1]. None of the tumor cells from 22 patients showed any reaction either with the SV40 T antibody or with the anti agnoprotein antibody [Figure 2]. The details of reactions are depicted in [Table 1]. It was interesting to note that the morphology of the tumor cells also did not show gross nuclear atypia, giant nuclei, or giant cells i.e., the features observed in patients with PML where oligodendrocytes and astrocytes are infected with the JC virus.


   Discussion Top


The JC virus infects the upper respiratory tract, remains dormant and produces disease only in the face of severe immune suppression in the host. In patients with AIDS, JC virus replication in oligodendrocytes results in a fatal demyelinating disease called PML. [1] Various brain tumors like medulloblastomas, astrocytomas glioblastomas and pituitary tumors [12],[17],[18] have also been linked to the JC virus. It contains an open reading frame within the late region of the viral genome that encodes a 71-amino-acid protein i.e., the agnoprotein. Other early antigens are T antigens, which are essential for viral replication. Agnoprotein has the capacity to be associated with the T antigen having oncogenic potential and communication between these two viral proteins is regarded as crucial for the induction of brain tumors. In 2001, Del Valle, et al. [19] examined 85 clinical samples from different centers and demonstrated the presence of early viral sequences in 49 out of 71 cases (69%). In another study, [20] the authors detected the agno gene sequence in 11 out of 16 samples. These authors postulated that the T antigen when complexed with agnoprotein enhances transcriptional activity and may cause brain tumors because of its oncogenic potential and in part by blocking the tumor suppressor genes pRb and p53.

In India, no data is available on the epidemiology of the JC virus except for one negative report by Engel, et al . [21] An attempt was therefore made to confirm if medulloblastomas are indeed associated with JC virus infection. None of the samples showed evidence of either T antigen or agnoprotein. The study, thus, does not support a role for JC virus in medulloblastomas in this part of India, a fact at variance with the observations made by several other investigators.

Two negative studies from India are intriguing. A serious question in any such setting is whether the virus has a causal relationship or is an opportunistic virus. There could also be geographic and genetic factors contributing as co-factors in these tumors, which may account for the lack of JC virus in Indians children with medulloblastomas.

However, Eberhart, et al. [13] from the U.S.A. could not substantiate the presence of the JC virus even in anaplastic medulloblastomas or primitive neuroectodermal tumors (PNET). In a study from this center, SV40 large T antigen of BK virus has been documented on immunohistochemistry in kidneys in 9.3% of patients with renal transplant dysfunction. [22]

The JC virus has also been linked to osteosarcomas and mesotheliomas, [23] colorectal cancer and colorectal xenografts raised in nude mice and the human colon cancer cell line SW 480. [24] JC virus and BK polyoma viruses have been well known to be associated with post transplant graft loss. [25],[26] In a recent study, BK regulatory sequences have been detected in a case of the human polyoma virus associated interstitial nephritis [27] but no renal neoplastic disease has been documented with the polyoma virus yet.

In patients with AIDS and those undergoing transplantation, it induces inflammatory and degenerative lesions rather than proliferative lesions or tumors. Patients with AIDS and PML are not known to be at added risk of developing brain tumors apart from ebstein-barr virus (EBV)- driven lymphomas. [28]

It thus appears that it may be a cofactor rather than the sole causal factor in these tumors in some geographic areas and these co-factors may be missing in Indian children with medulloblastomas. In fact, in a more recent study, Munroz Marmol, et al. [29] also pointed towards the rarity of the JC virus DNA sequences and early proteins in brain tumors thus reaffirming the controversial role of the JC virus in human neuro-oncogenesis. This study could not substantiate an authentic role of JC virus in Indian children with medulloblastomas.

 
   References Top

1.Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 1992;5:49-73.   Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Berger JR, Concha M. Progressive multifocal leukoencephalopathy: The evolution of a disease once considered rare. J Neurovirol 1995;1:5-18.  Back to cited text no. 2  [PUBMED]  
3.Berger JR, Chauhan A, Galey D, Nath A. Epidemiological evidence and molecular basis of interaction between HIV and JC virus. J Neurovirol 2001;7:329-38.  Back to cited text no. 3  [PUBMED]  
4.Shah KV. Polyoma viruses in Medical Virology Ed. Fields BN, Knippe D, New York (NY). Raven press 1990:1609-24.  Back to cited text no. 4    
5.Walker DL, Padgett BL, Zu Rhein GM, Albert AE, Marsh RF. Human papovavirus (JC): induction of brain tumors in hamsters. Science 1973;181:674-6.  Back to cited text no. 5    
6.London WT, Houff SA, Madden DL, Fuccillo DA, Gravell M, Wallen WC, et al . Brain tumors in owl monkeys inoculated with a human polyomavirus (JCvirus). Science 1978;201:1246-9.   Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Krynska B, Otte J, Franks R, Khalili K, Croul S. Human ubiquitous JCV(CY)T antigen gene induces brain tumors in experimental animals. Oncogene 1999;18:39-46.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Small JA, Khoury G, Jay G, Howley PM, Scangos GA. Early regions of JC virus and BK virus induce distinct and tissue-specific tumors in transgenic mice. Proc Natl Acad Sci USA 1986;83:8288-92.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
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10.Dyson N, Bernards R, Friend SH, Gooding LR, Hassle JA, Major EO, et al . Large T antigen of many polyoma viruses are able to form complexes with the retinoblastoma protein. J Virol 1990;64:1353-6.   Back to cited text no. 10    
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12.Del Valle L, Azizi SA, Krynska B, Enam S, Croul SE, Khalili K. Reactivation of human neurotropic JC virus expressing oncogenic protein in recurrent glioblastoma multiforme. Ann Neurol 2000;48:932-6.  Back to cited text no. 12  [PUBMED]  
13.Eberhart CG, Chaudhry A, Daniel RW, Khaki L, Shah KV, Gravitt PV. Increased p53 immuno positivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus. BMC cancer 2005;5:5-19.  Back to cited text no. 13    
14.Shankar SK, Satishchandra P, Madhvan A, Yasha TC, Nagaraja D, Taly AB, et al . Low prevalence of progressive multifocal leucoencephalopathy in India and Africa: is there a biological explanation? J Neurovirol 2003;9:59-67.  Back to cited text no. 14    
15.Sood A, Sharma M, Sehgal S, Kumar B, Varma S. Spectrum of co infections in HIV positive patients in north India. J Nat Acad Med Sci New Delhi 1999;35:151-8.  Back to cited text no. 15    
16.WHO Classification of Tumors of the Central Nervous System. Ed. Louis DN, Ohgaki H, Weistler OD and Cavenee WK. International Agency for Research on Cancer, Lyon 2007:132-40.  Back to cited text no. 16    
17.Gordon J, Del Valle L, Otte J, Khalili K. Pituitary neoplasia induced by expression of human neurotropic virus JCV, early genome in transgenic mice. Oncogene 2000;19:4840-6.   Back to cited text no. 17  [PUBMED]  [FULLTEXT]
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19.Del Valle L, Gordon J, Assimakopoulou M, Enam S, Geddes JF, Varakis JN, et al . Detection of JC virus DNA sequences and expression of the viral regulatory protein T-antigen in tumors of the central nervous system. Cancer Res 2001;61:4287-93.   Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Del Valle L, Gordon J, Enam S, Delbue S, Croul S, Abraham S, et al . Expression of human neurotropic Polyomavirus JCV late gene product agnoprotein in human medulloblastoma. J Natl Cancer Inst 2002;94:267-73.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Engels EA, Sarkar C, Daniel RW, Gravitt PE, Verma K, Quezado M, et al . Absence of simian virus 40 in human brain tumors from northern India. Int J Cancer 2002;101:348-52.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Sachdeva MS, Nada R, Jha V, Sakhuja V, Joshi K. High incidence of BK polyoma virus infection among renal transplant recipients in India. Transplantation 2004;77:429-31.   Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Strickler HD, Goedert JJ, Flemming M, Travis WD, Williams AE, Rabkin CS. Simian SV 40 and pleural mesothelioma in humans. Cancer Epidemiol Biomarkers Prev 1996;6:473-5.  Back to cited text no. 23    
24.Laghi L, Raudolf AE, Chauhan PD, Marva G, Major EO, Neel JV, et al . J C virus DNA is present in the mucosa of the human colon and in colorectal cancers. Proc Natl Acad Sci U S A 1999;96:7484-9.  Back to cited text no. 24    
25.Randhawa P, Baksh F, Aoki N, Tschirhart D, Finkelstein S. J C virus infection in allograft kidneys. Transplantation 2003;71:1300-3.  Back to cited text no. 25    
26.Manna P, Vats A. Is JC viral disease being overlooked: An examination of prevalence and magnitude of different polyomaviral loads. Am Soc of Nephrol 2003; Abstract number: SA-FC190 Nov 15.   Back to cited text no. 26    
27.Azzi A, De santis R, Salotti V, Dipietro N, Ginevii F, Comoli P. BK virus regulatory sequences detected in a case of human polyoma virus associated interstitial nephriris. J Clin Virol 2006;35:106-8.  Back to cited text no. 27    
28.MacMohan EM, Glass JD, Hayward SD, Mann RB, Becker PS, Charache P, et al . Epstein Barr virus in AIDS related primary central nervous system lymphoma. Lancet 1991;338:969-73.  Back to cited text no. 28    
29.Munroz Marmol AM, Mola G, Ruiz-Larroya T, Fernαndez-Vasalo A, Vela E, Mate JL, et al . Rarity of JC virus DNA sequences and early proteins in human gliomas and medulloblastomas: The controversial role of JC virus in human neuro oncogenesis. Neuropathol Appl Neurobiol 2006;32:131-40.  Back to cited text no. 29    

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Correspondence Address:
Shobha Sehgal
Department of Immunopathology, PGIMER, Chandigarh 160 012, UT
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.44961

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