Donor‐derived, metastatic urothelial cancer after kidney transplantation associated with a potentially oncogenic BK polyomavirus

Abstract

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 showed no key driver mutations as assessed by next-generation sequencing. Whole genome sequencing and BK polyomavirus-specific amplification provided evidence for episomal and subgenomic chromosomally integrated BK polyomavirus genomes, which carried the same unique 17-bp 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 17-bp 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 large tumour antigen and small tumour antigen from episomal and integrated gene expression. Surgery combined with discontinuation of immunosuppression resulted in complete remission, but sacrificed the renal transplant. Thus, this report links, for the first time, BK polyomavirus NCCR rearrangements with oncogenic transformation in urothelial cancer in immunosuppressed patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Characterization of six Merkel cell polyomavirus‐positive Merkel cell carcinoma cell lines: Integration pattern suggest that large T antigen truncating events occur before or during integration

“…However, also in these cancer cells the BKPyV‐integration process seems to be accompanied by changes in the viral genome precluding viral replication. In particular loss of VP1 coding sequence and deletions in the NCCR have been described . In one case, such a deletion which was present both in an episomal and integrated viral genome was shown to confer decreased viral replication capacity but increased T‐antigen expression .…”

“…In particular loss of VP1 coding sequence and deletions in the NCCR have been described. 43,44 In one case, such a deletion which was present both in an episomal and integrated viral genome was shown to confer decreased viral replication capacity but increased T-antigen expression. 43 Similarly, increased T-antigen expression has also been described for clinically occurring NCCR rearrangements in HPyV7 and HPyV9.…”

Unusual BK polyomavirus‐associated urologic malignancies in renal transplant recipients: Report of two cases and review of the literature

“…However, the most serious complication of BKV in these patients is the development of urologic malignancies. Fortunately, such complications are rare and only 36 cases of urothelial carcinoma (UC) (Table ), and several renal cell carcinomas, including collecting duct carcinomas were reported to date …”

High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis

“…However, recent genomic studies have suggested, or at least produced findings consistent with, the idea that BK polyomavirus may contribute to tumorigenesis through viral integration into the host genome and expression of viral oncoproteins (e.g. polyoma T‐antigen) . From the standpoint of the differential diagnosis with bona fide CDC, our experience with ongoing studies of a cohort of these tumors is that they most frequently are urothelial carcinomas; however, they often show variant differentiation, which can include glandular patterns entering the differential diagnosis with CDC (Fig.…”

“…Anecdotal experience suggests that such cases may show a more urothelial pattern of differentiation, sometimes with “glassy” nuclear changes suggestive of viral cytopathic effect, with expression of markers such as GATA3 and p63, diffuse nuclear p53, and diffuse IHC expression using antibodies against T‐antigen . Recognition of the phenomenon is important, given better established therapy for urothelial carcinoma compared to CDC, and given reports of resolution of even metastatic disease upon cessation of immunosuppression . We suspect that with increasing scholarship and experience, BK‐related tumors with infiltrative glandular pattern that have been considered CDC previously would come to be excluded from this group.…”