title: 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.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
authors.forename: Narayan
authors.initials: N
authors.lastname: Shivapurkar
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Reddy
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.forename: Victor
authors.initials: V
authors.lastname: Stastny
authors.forename: Robert
authors.initials: R
authors.lastname: Collins
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Makato
authors.initials: M
authors.lastname: Suzuki
authors.forename: Gunjan
authors.initials: G
authors.lastname: Parikh
authors.forename: Sheryl
authors.initials: S
authors.lastname: Asplund
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kroft
authors.forename: Charles
authors.initials: C
authors.lastname: Timmons
authors.forename: Robert W
authors.initials: RW
authors.lastname: McKenna
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D019175:DNA Methylation; D004279:DNA, Viral / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000235:genetics* / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000821:virology; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000235:genetics* / Q000821:virology; D011401:Promoter Regions, Genetic; D013539:Simian virus 40 / Q000235:genetics*
chemical_list: D004279:DNA, Viral