BK polyomavirus has been linked to urothelial carcinoma in immunosuppressed patients. Here, we performed comprehensive genomic analysis of a BK polyomavirus -associated, metachronous, multifocal and metastatic micropapillary urothelial cancer in a kidney transplant recipient. Dissecting cancer heterogeneity by sorting technologies prior to array-comparative genomic hybridization followed by short tandem repeat analysis revealed that the metastatic urothelial cancer was of donor-origin (4 year-old male). The top 50 cancer-associated genes displayed no key driver mutations as assessed by next generation sequencing. Whole genome sequencing and BK polyomavirus-specific amplification provided evidence for episomal and sub-genomic chromosomally integrated BK polyomavirus genomes, which carried the same unique 17bp-deletion signature in the viral non-coding control region (NCCR). Whereas no role in oncogenesis could be attributed to the host gene integration in chromosome 1, the 17bp-deletion in the NCCR increased early viral gene expression, but decreased viral replication capacity. Consequently, urothelial cells were exposed to high levels of the transforming BK polyomavirus early proteins LTag and sTag from episomal and integrated gene expression. Surgery combined with discontinuing immunosuppression resulted in complete remission, yet sacrificing the renal transplant. Thus, this report links for the first time BK polyomavirus NCCR-rearrangements with oncogenic transformation in urothelial cancer in immunosuppressed patients.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AVladq
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