Presence of Simian Virus 40 DNA Sequences in Human Lymphoid and Hematopoietic Malignancies and Their Relationship to Aberrant Promoter Methylation of Multiple Genes

Abstract

The simian polyoma virus SV40 has been detected in specific human tumors including non-Hodgkin's lymphomas, although a causative role for the virus has not been convincingly demonstrated. Aberrant methylation of CpG islands in promoter regions is a frequent method of silencing tumor suppressor genes (TSGs) in cancers and may be induced by oncogenic viruses. We investigated the relationship between the presence of SV40 or EBV DNA sequences and the methylation profiles for 10 TSGs in 90 cases of non-Hodgkin's lymphomas/leukemias and 56 control tissues. SV40 sequences were present in 33/90 (37%) non-Hodgkin's lymphomas/leukemias, and EBV was present in 11/42 (26%) of non-Hodgkin's lymphomas. We found a highly significant correlation between the presence of SV40 and methylation of seven genes (P values, 0.006 to <0.0001). In lymphomas, there was no relationship between EBV and methylation. Oncogenic viruses and methylation were rarely present in control tissues. We investigated methylation of the same 10 TSGs in peripheral blood mononuclear cells (PBMC) from a healthy volunteer infected with EBV or EBV and SV40. Promoter methylation of CDH1 and CDH13 were noted in dual SV40-and EBV-infected PBMC, and these two genes were also highly significantly correlated to the presence of SV40 sequences in tumors. SV40 infection also resulted in appearance of the lymphoma/leukemia-specific marker, methylated SHP1. Methylation was completely absent in uninfected and EBV-infected PBMC. Our results demonstrate that the presence of SV40 in hematological malignancies is associated with promoter methylation of TSGs and that in all probability, the virus plays a role in tumor pathogenesis.

Presence of simian virus 40 DNA sequences in diffuse large B‐cell lymphomas in Tunisia correlates with aberrant promoter hypermethylation of multiple tumor suppressor genes

“…Using PCR and subsequent Southern blotting, we have successfully demonstrated the presence of SV40 DNA sequences in 56% of DLBCLs in Tunisian patients prevalence, which is at the higher end of those reported from other countries. [12][13][14][15][16][17][18][19][20][21] However, these findings are at variance with those presented by other investigators, [22][23][24] who did not detect SV40 DNA in any of the lymphomas samples analyzed. This discrepancy in SV40 detection in lymphoma between several parts of the world is not clear, but it could be at least in part due to differences in laboratory techniques used for virus detection, the criteria of requirements for confirmation of the presence of virus, 1,19,22,54,56 the characteristics of patients populations that were the source of specimens 1,54 and mainly the difference in histological types of lymphomas tested.…”

“…28 One interesting recent study has reported a correlation between promoter hypermethylation of several TSGs and the presence of SV40 DNA in a heterogeneous group of leukemias and lymphomas, suggesting that SV40 might cause DNA methylation of TSGs. 15 In this study, we investigate the presence of SV40 DNA sequences in 108 cases of DLBCLs from patients from Tunisia and correlate the data with methylation status of a panel of 13 TSGs known or suspected to be altered by hypermethylation in several cancers including lymphomas. These tested genes included those involved in cell-cycle regulation (p14, p15, p16, p53 and RB1), cell invasion and adhesion (APC and CDH1), DNA repair and detoxification (MGMT and GSTP1), apoptosis (DAPK), B-cell differentiation (SHP1) and cell growth (p300 and BLU).…”

“…[2][3][4] SV40 DNA sequences have been detected in pediatric and adult brain tumors, 5,6 mesotheliomas, 7 osteosarcomas, 8 bronchopulmonary carcinomas, 9 bone tumors 10 and papillary thyroid carcinomas. 11 There also increasing evidence that SV40 is associated with non-Hodgkin's lymphomas, particularly with diffuse large B-cell lymphomas (DLBCL), [12][13][14][15][16][17][18][19][20][21] in spite of several negative studies. [22][23][24] However, although these observations indicate an association between this virus and specific human tumors, they do not demonstrate a causal role, and the molecular mechanism by which SV40 thought to be involved is still unclear.…”

Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion

“…Inflammation associated with bacterial or viral infection is a well-known cause of methylation of some genes. [22][23][24] In some cases, DAPK methylation conceivably might have been induced by pneumonia or tuberculous pleuritis. In addition, a reported observation that hypermethylation of 6 genes including RASSF1A, p16, and DAPK was absent in 8 peritoneal fluid DNA samples from patients with ovarian cysts supports our speculation that inflammation is associated with methylation of some genes.…”

Presence of simian virus 40 in diffuse large B-cell lymphomas in Tunisia correlates with germinal center B-cell immunophenotype, t(14;18) translocation, and P53 accumulation

“…16,17 Previous reports, however, have failed to demonstrate any correlation between P53 accumulation in diffuse large B-cell lymphomas and several oncogenic viruses, including Epstein-Barr virus. [18][19][20] Several studies from the United States, [21][22][23] Japan, 24 Costa Rica, 25 and Taiwan 26 have successfully detected simian virus 40 (SV40) DNA by PCRbased methods in variable proportions of nonHodgkin's lymphomas, mainly diffuse large B-cell lymphomas, ranging from 11 to 62% of cases. We have recently 27 reported a high prevalence of SV40 in diffuse large B-cell lymphomas occurring in Tunisian patients (56%), and we noted that the presence of SV40 was significantly correlated with aberrant promoter hypermethylation of several tumor suppressor genes, suggesting a functional effect of this virus in those lymphomas.…”