title: The oncogenic potential of BK-polyomavirus is linked to viral integration into the human genome.
abstract: It has been suggested that BK-polyomavirus is linked to oncogenesis via high expression levels of large T-antigen in some urothelial neoplasms arising following kidney transplantation. However, a causal association between BK-polyomavirus, large T-antigen expression and oncogenesis has never been demonstrated in humans. Here we describe an investigation using high-throughput sequencing of tumour DNA obtained from an urothelial carcinoma arising in a renal allograft. We show that a novel BK-polyomavirus strain, named CH-1, is integrated into exon 26 of the myosin-binding protein C1 gene (MYBPC1) on chromosome 12 in tumour cells but not in normal renal cells. Integration of the BK-polyomavirus results in a number of discrete alterations in viral gene expression, including: (a) disruption of VP1 protein expression and robust expression of large T-antigen; (b) preclusion of viral replication; and (c) deletions in the non-coding control region (NCCR), with presumed alterations in promoter feedback loops. Viral integration disrupts one MYBPC1 gene copy and likely alters its expression. Circular episomal BK-polyomavirus gene sequences are not found, and the renal allograft shows no productive polyomavirus infection or polyomavirus nephropathy. These findings support the hypothesis that integration of polyomaviruses is essential to tumourigenesis. It is likely that dysregulation of large T-antigen, with persistent over-expression in non-lytic cells, promotes cell growth, genetic instability and neoplastic transformation.
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kenan
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.affiliation: School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Burger-Calderon
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Harsharan K
authors.initials: HK
authors.lastname: Singh
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Volker
authors.initials: V
authors.lastname: Nickeleit
mesh_terms: D064591:Allografts; D000957:Antigens, Viral, Tumor / Q000235:genetics; D001739:BK Virus / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D001706:Biopsy; D036022:Capsid Proteins / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery / Q000821:virology; D002352:Carrier Proteins / Q000235:genetics; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002881:Chromosomes, Human, Pair 12; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery / Q000821:virology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D027601:Polyomavirus Infections / Q000821:virology*; D014412:Tumor Virus Infections / Q000821:virology*; D019459:Urothelium / Q000473:pathology / Q000821:virology; D016662:Virus Integration; D014779:Virus Replication; D000099163:Myosin Binding Protein C
chemical_list: D000957:Antigens, Viral, Tumor; D036022:Capsid Proteins; D002352:Carrier Proteins; D009856:Oncogene Proteins, Viral; D000099163:Myosin Binding Protein C; C062481:VP1 protein, polyomavirus
keywords: BK virus; carcinoma; cell transformation, neoplastic; kidney transplantation; large T Antigen; oncogenesis; polyomavirus; polyomavirus nephropathy; virus integration