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Abstract: FR-PO790

Distinct Mutation Patterns in BK Polyomavirus Genome-Integrated Urothelial Carcinomas and Urothelial Carcinomas with Mutational Signature of Aristolochic Acid

Session Information

Category: Transplantation

  • 2102 Transplantation: Clinical

Author

  • Tian, Ya-chung, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
Background

Urothelial carcinoma (UC) is highly prevalent among kidney transplant recipients in certain regions and may be linked to the integration of BK polyomavirus (BKPyV) genome into the human genome. In Taiwan, a high prevalence of aristolochic acid (AA) mutational signatures in UC was exhibited in general population. To better understand these etiologies in UC oncogenesis in kidney transplant patients, whole-genome sequencing (WGS) was employed to determine the integration of BK polyomavirus (BKPyV) genome into the human genome and AA mutational signatures in UC.

Methods

Twenty UC specimens underwent WGS analysis to evaluate BKPyV genome integration and AA mutational signatures, with Sanger sequencing used for confirmation of BKPyV genome integration.

Results

Twenty UC specimens underwent WGS analysis to evaluate BKPyV genome integration and AA mutational signatures, with Sanger sequencing used for confirmation in UC specimens with BKPyV genome integration.
Results: BKPyV genome integration was found in 7 out of 20 UC specimens (37%), while 16 out of 20 UC specimens (80%) contained the AA mutation signature. Three specimens (15%) had both characteristics. A total of 106 integration sites in UC specimens with BKPyV genome integration were identified. Most of the integration sites were located in introns and intergenic regions, with only two sites in exons. Notably, a specific integration site with a breakpoint at TAg4289 of the BKPyV genome and at the intron of the human eukaryotic translation initiation factor 2B subunit alpha (EIF2B1) was observed in three distinct UC specimens, and this finding was confirmed via Sanger sequencing. The WGS results also revealed a high prevalence (80%) of the AA mutational signature in these UC specimens. A high percentage of UC cases exhibited mutations in genes related to chromatin modification (KMT2C, 70%), the cell-cycle pathway (TP53, 55%), and the RTK-PI3K pathway (ERBB2, 25%). Interestingly, UC cases with BKPyV genome integration had significantly lower total mutation burden and fewer mutations in these genes compared to those with the AA mutational signature, suggesting distinct mechanisms of carcinogenesis in UC.

Conclusion

In conclusion, our findings provide compelling evidence for different mechanisms underlying the development of UC in Taiwanese kidney transplant recipients.