title: BK Polyomavirus Genomic Integration and Large T Antigen Expression: Evolving Paradigms in Human Oncogenesis.
abstract: Human polyomaviruses are ubiquitous, with primary infections that typically occur during childhood and subsequent latency that may last a lifetime. Polyomavirus-mediated disease has been described in immunocompromised patients; its relationship to oncogenesis is poorly understood. We present deep sequencing data from a high-grade BK virus-associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft 6 years after transplantation. We identified a novel genotype 1a BK polyomavirus, called Chapel Hill BK polyomavirus 2 (CH-2), that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral break points were found, disrupting late BK gene sequences encoding capsid proteins VP1 and VP2/3. Immunohistochemistry and in situ hybridization studies demonstrated that the integrated BK virus was replication incompetent. We propose that the BK virus CH-2 was integrated into the human genome as a concatemer, resulting in alterations of feedback loops and overexpression of large T antigen. Collectively, these findings support the emerging understanding that viral integration is a nearly ubiquitous feature in polyomavirus-associated malignancy and that unregulated large T antigen expression drives a proliferative state that is conducive to oncogenesis. Based on the current observations, we present an updated model of polyomavirus-mediated oncogenesis.
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC.
authors.forename: D J
authors.identifier: http://orcid.org/0000-0002-5284-7284
authors.initials: DJ
authors.lastname: Kenan
authors.affiliation: Department of Genetics, The University of North Carolina, Chapel Hill, NC.
authors.forename: P A
authors.initials: PA
authors.lastname: Mieczkowski
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Centre Hospitalier Universitaire de Québec, Hôtel Dieu de Québec, Québec, PQ, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Latulippe
authors.affiliation: Division of Nephrology, Department of Medicine, Centre Hospitalier Universitaire de Québec, Hôtel Dieu de Québec, Québec, PQ, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Côté
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC.
authors.forename: H K
authors.initials: HK
authors.lastname: Singh
authors.affiliation: Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC.
authors.forename: V
authors.initials: V
authors.lastname: Nickeleit
mesh_terms: D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D001739:BK Virus / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D015894:Genome, Human; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections / Q000150:complications* / Q000235:genetics / Q000821:virology; D011379:Prognosis; D014412:Tumor Virus Infections / Q000150:complications* / Q000235:genetics / Q000821:virology; D016662:Virus Integration / Q000235:genetics*; D014779:Virus Replication
chemical_list: D000957:Antigens, Viral, Tumor
keywords: basic (laboratory) research/science; cancer/malignancy/neoplasia; clinical research/practice; infection and infectious agents; infectious disease; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; molecular biology: DNA; pathology/histopathology; viral: BK/JC/polyoma