BK Polyomavirus Genomic Integration and Large T Antigen Expression: Evolving Paradigms in Human Oncogenesis |
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| Authors: | D. J. Kenan P. A. Mieczkowski E. Latulippe I. Côté H. K. Singh V. Nickeleit |
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| Affiliation: | 1. Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC;2. Department of Genetics, The University of North Carolina, Chapel Hill, NC;3. Division of Pathology, Department of Laboratory Medicine, Centre Hospitalier Universitaire de Québec, H?tel Dieu de Québec, Québec, PQ, Canada;4. Division of Nephrology, Department of Medicine, Centre Hospitalier Universitaire de Québec, H?tel Dieu de Québec, Québec, PQ, Canada |
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| 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. |
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| Keywords: | basic (laboratory) research/science clinical research/practice kidney transplantation/nephrology infectious disease pathology/histopathology infection and infectious agents viral: BK/JC/polyoma kidney (allograft) function/dysfunction molecular biology: DNA cancer/malignancy/neoplasia |
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