The presence of JC virus in gastric carcinomas correlates with patient's age, intestinal histological type and aberrant methylation of tumor suppressor genes

Department of Pathology, Farhat-Hached Hospital of Sousse, Sousse, Tunisia.
Modern Pathology (Impact Factor: 6.19). 04/2010; 23(4):522-30. DOI: 10.1038/modpathol.2009.184
Source: PubMed


JC virus (JCV) is a neurotropic polyomavirus and the causative agent of progressive multifocal leukoencephalopathy. A role for JCV in gastrointestinal malignancies has been recently suggested. This study was carried out to determine the prevalence of polyomaviruses including JCV, BKV and SV40 in gastric cancers in Tunisia and to determine the clinicopathological characteristics of virus-associated gastric carcinomas. The presence of polyomaviruses DNA sequences was surveyed in 61 cases of primary gastric carcinomas and in 53 paired non-tumor gastric mucosa by PCR. Findings were correlated to clinicopathological parameters, p53 expression and methylation status of 11 tumor-related genes. Using PCR assays, JCV T-antigen sequence was more frequently detected in gastric carcinomas than in non-tumor gastric mucosa (26 vs 6%, P=0.03), while those of SV40 and BKV were not detected in any cases. Correlation analysis showed that JCV had higher frequency in patients older than 55 years (P=0.034) and in the intestinal histological type (P=0.04). With regard to methylation status, P16 and P14 showed significantly higher methylation frequencies in JCV-positive gastric carcinomas than in JCV-negative cases (P=0.007 and P=0.003, respectively). Moreover, the mean of the methylation index was significantly higher in JCV-positive than in JCV-negative cases (P=0.024). In multivariate logistic regression analysis, age of patients and the methylation index are only the two independent factors associated with JCV infection. Kaplan-Meier survival analysis showed a trend toward better survival for JCV-associated gastric carcinomas patients (log-rank, P=0.11). Our study suggests a role of JCV as cofactor in the pathogenesis of the intestinal type of gastric carcinomas in older persons.

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    • "Importantly, Bofill-Mas, et al showed that viral particles isolated from sewage remained intact after treatment at a pH of 1 for 30 minutes, indicating that ingestion of contaminated water or food may be sufficient for JCV infection of the gastrointestinal tract [20]. Many studies since, have demonstrated the presence of JCV genomic sequences and the expression of T-Antigen in tissues from gastrointestinal tumors, including esophageal carcinoma [11], gastric carcinoma [12], [21], [22], sporadic adenomatous polyps [23], and colorectal adenocarcinomas [10], [24]–[30]. "
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    ABSTRACT: During the last decade, mounting evidence has implicated the human neurotropic virus JC virus in the pathology of colon cancer. However, the mechanisms of JC virus-mediated oncogenesis are still not fully determined. One candidate to mediate these effects is the viral early transcriptional product T-Antigen, which has the ability to inactivate cell cycle regulatory proteins such as p53. In medulloblastomas, T-Antigen has been shown to bind the Wnt signaling pathway protein β-catenin; however, the effects of this interaction on downstream cell cycle regulatory proteins remain unknown. In light of these observations, we investigated the association of T-Antigen and nuclear β-catenin in colon cancer cases and the effects of this complex in the activation of the transcription and cell cycle regulators c-Myc and Cyclin D1 in vitro. Gene amplification demonstrated the presence of viral sequences in 82.4% of cases and we detected expression of T-Antigen in 64.6% of cases by immunohistochemistry. Further, we found that T-Antigen and β-catenin co-localized in the nuclei of tumor cells and we confirmed the physical binding between these two proteins in vitro. The nuclear presence of T-Antigen and β-catenin resulted in the significant enhancement of TCF-dependent promoter activity and activation of the β-catenin downstream targets, c-Myc and Cyclin D1. These observations provide further evidence for a role of JCV T-Antigen in the dysregulation of the Wnt signaling pathway and in the pathogenesis of colon cancer.
    Full-text · Article · Sep 2014 · PLoS ONE
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    ABSTRACT: The human neurotropic polyomavirus JC virus (JCV) is a small DNA tumor virus and the established etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV is widely distributed among the human population, as greater than 80% of adults exhibit JCV-specific antibodies. After initial infection early in life, the virus establishes a persistent nonpathogenic infection in the normal host. In patients with disruptions in the immune system, the virus can undergo reactivation and subsequently cause lytic destruction of oligodendrocytes resulting in PML. In a cellular context that is nonpermissive for viral replication, JCV can contribute to oncogenic transformation. Accordingly, evidence suggests that JCV can induce a variety of tumor types in experimental animals and has been associated with neural and nonneural types of malignancies in humans. Although JCV is considered a neurotropic virus due to its association with PML, it is well-established that the virus persists in the kidney, tonsils, and lymphoid tissues and has been detected in the bone marrow and peripheral blood cells. It is presumed that the blood stream can serve as a conduit to propagate the virus into different organs, including the brain. Given the transforming ability and ubiquitous nature of JCV, it is possible that JCV plays a critical role in the induction of human cancer. However, it remains unknown whether JCV has a causal role in human cancer. In this chapter, we discuss the tumorigenic potential of JCV with special emphasis on the potential role of bone marrow-derived stem cells in the pathogenesis of JCV-associated diseases.
    No preview · Article · Jan 2012 · Current Cancer Research
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    ABSTRACT: JCV is a DNA polyomavirus very well adapted to humans. Although JCV DNA has been detected in colorectal cancers (CRC), the association between JCV and CRC remains controversial. In China, the presence of JCV infection in CRC patients has not been reported. Here, we investigated JCV infection and viral DNA load in Chinese CRC patients and to determine whether the JCV DNA in peripheral blood (PB) can be used as a diagnostic marker for JCV-related CRC. Tumor tissues, non-cancerous tumor-adjacent tissues and PB samples were collected from 137 CRC patients. In addition, 80 normal colorectal tissue samples from patients without CRC and PB samples from 100 healthy volunteers were also harvested as controls. JCV DNA was detected by nested PCR and glass slide-based dot blotting. Viral DNA load of positive samples were determined by quantitative real-time PCR. JCV DNA was detected in 40.9% (56/137) of CRC tissues at a viral load of 49.1 to 10.3×10(4) copies/µg DNA. Thirty-four (24.5%) non-cancerous colorectal tissues (192.9 to 4.4×10(3) copies/µg DNA) and 25 (18.2%) PB samples (81.3 to 4.9×10(3) copies/µg DNA) from CRC patients were positive for JCV. Tumor tissues had higher levels of JCV than non-cancerous tissues (P = 0.003) or PB samples (P<0.001). No correlation between the presence of JCV and demographic or medical characteristics was observed. The JCV prevalence in PB samples was significantly associated with the JCV status in tissue samples (P<0.001). Eleven (13.8%) normal colorectal tissues and seven (7.0%) PB samples from healthy donors were positive for JCV. JCV infection is frequently present in colorectal tumor tissues of CRC patients. Although the association between JCV presence in PB samples and JCV status in tissue samples was identified in this study, whether PB JCV detection can serve as a marker for JCV status of CRC requires further study.
    Full-text · Article · May 2012 · PLoS ONE
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