Occurrence and regression of BK polyomavirus associated carcinoma: a clinical and next-generation sequencing study

Abstract

Low-level BK polyomavirus (BKPyV) shedding is seen in at least 10% of seropositive immunocompetent adults. Moreover, BKPyV infection is highly prevalent amongst immunocompromised populations, yet little is known on its relationship with malignancy. We studied a female patient with BKPyV-associated and donor-derived high-grade sarcomatoid urothelial carcinoma developed 8 years after kidney transplantation from a male donor. Through whole-genome sequencing, we discovered integration of genotype IV BKPyV genome into the non-coding RNA (ncRNA) intronic region of human chromosome 18. The two breakpoints in the virus genome were located at the non-coding control region (NCCR) and large T antigen (TAg) coding region, respectively. Nevertheless, the TAg was overexpressed. We, therefore, inferred that the BKPyV was clonally integrated into the human genome in the form of concatemers, facilitating the expression of the TAg. The patient presented with multiorgan metastases, which were reduced in size and number throughout the body after removal of the graft and cessation of immunosuppressants. The few remaining lesions located in the liver were identified, through biopsy to be necrotic tumor tissue with TAg detected; additionally, genomic sequencing of the liver mass found Y chromosome. In conclusion, we propose that integration of the BKPyV genome is closely related to oncogenesis in this patient; while oncogenesis occurred when host immunity was impaired, recovery of the patient's native immunity effectively curbed viral replication and eliminated the metastatic lesions.

BK polyomavirus infection promotes growth and aggressiveness in bladder cancer

“…In recent years, the correlation between BKPyV infection and tumorigenesis in immunocompromised individuals has drawn increased attention. The idea that BKPyV plays an important role in cancers of the urinary system was recently confirmed by deep sequencing studies, which confirmed that the BKPyV gene was integrated into the genome of renal cancer and urothelial carcinoma cells after transplantation [13][14][15]. Besides, Querido et al showed that JCpyV may cause urothelial carcinoma after transplant [25], which also supports the argument that human polyomavirus is closely related to bladder cancer.…”

“…Many recent studies detected BKPyV gene integration in urinary tract epithelial cell tumors, providing further evidence for the correlation between BKPyV and urinary tract tumors [8,[12][13][14][15][16][17]. Interestingly, almost all of these integrations occurred in post-transplant tumors, but not in nontransplant tumors [17].…”

“…Therefore, BKPyV reactivation in immunosuppressed environments may be considered as a transforming factor leading to urothelial carcinomas. In addition, some studies have shown that transplant recipients with BKPyV viremia or polyomavirus-associated kidney disease have an increased risk (4-11 times) of bladder cancer when compared to transplant recipients without BKPyV [14,18]. Although the underlying role of BKPyV in human cancers has not been fully determined, the close relationship between BKPyV and the development of urothelial cancer after transplantation, is without question.…”

BK polyomavirus infection promotes growth and aggressiveness in bladder cancer

“…In recent years, the correlation between BKPyV infection and tumorigenesis in immunocompromised individuals has drawn increased attention. The idea that BKPyV plays an important role in cancers of the urinary system was recently con rmed by deep sequencing studies, which con rmed that the BKPyV gene was integrated into the genome of renal cancer and urothelial carcinoma cells after transplantation [13][14][15]. Besides, Querido et al showed that JCpyV may cause urothelial carcinoma after transplant [25], which also supports the argument that human polyomavirus is closely related to bladder cancer.…”

“…Many recent studies detected BKPyV gene integration in urinary tract epithelial cell tumors, providing further evidence for the correlation between BKPyV and urinary tract tumors [8,[12][13][14][15][16][17]. Interestingly, almost all of these integrations occurred in post-transplant tumors, but not in non-transplant tumors [17].…”