Abstract
BK polyomavirus (BKPyV)-associated cancer after transplantation has gained increasing attention. However, the role of BKPyV integration on oncogenesis is still unclear. In this study, next-generation virome capture sequencing of primary and metastatic tumors were performed in three patients with BKPyV-associated urothelial carcinoma after renal transplantation. As a result, a total of 332 viral integration sites were identified in the six tumors. Integration of BKPyV in both primary and metastatic tumors followed the mechanism of microhomology-mediated end joining mostly, since microhomologies between human and BKPyV genomes were significantly enriched in flanking regions of 84% of the integration sites. Viral DNA breakpoints were nonrandom and tended to assemble in large T gene, small T gene and viral protein 2 gene. There were three, one and one consensus integration sites between the primary and metastatic tumors, which affected LINC01924, eIF3c, and NEIL2 genes in the three cases respectively. Thus, we concluded that integration of BKPyV was a continuous process occurring in both primary and metastatic tumors, generating heterogenous tumor cell populations. Through this ongoing process, certain cell populations might have gained growth advantage or metastatic potential, as a result of viral integration either affecting the cellular genes where the viral DNA integrated to or altering the expression or function of the viral genes.
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Data availability
Whole genome sequencing data of the six samples are available at NCBI Sequence ReadArchive with the BioProject accession number of PRJNA643598. Integration sites identified by capture sequencing were summarized in Supplementary Table S1. Virome capture sequencing data and probe sequences are available from the corresponding author on reasonable request.
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Acknowledgements
The work was funded by Natural Science Foundation of Guangdong Province [grant number 2020A1515010674], National Natural Science Foundation of China [grant number 81500573], Science and Technology Planning Project of Guangzhou [grant number 201803010109] and President Funding of Nanfang Hospital [grant number 2018B009, 2018C003]. And we thanked Dr. Min-Hua Luo (Wuhan Institute of Virology, Wuhan, China) for her assisstant in the study design and critical revision of the manuscript.
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Wang, Y., Liu, Y., Deng, W. et al. Viral integration in BK polyomavirus-associated urothelial carcinoma in renal transplant recipients: multistage carcinogenesis revealed by next-generation virome capture sequencing. Oncogene 39, 5734–5742 (2020). https://doi.org/10.1038/s41388-020-01398-6
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DOI: https://doi.org/10.1038/s41388-020-01398-6