Distinct subtypes of kidney transplant-associated urothelial carcinomas harboring BK polyomavirus integration and aristolochic acid mutational signatures.

Urothelial carcinoma (UC) is common in kidney transplant recipients, especially in Taiwan. Both BK polyomavirus (BKPyV) genome integration and aristolochic acid (AA) mutagenesis have been implicated in UC carcinogenesis, but their relative contributions remain unclear. To characterize the molecular features of UC in kidney transplant recipients, we performed whole-genome sequencing (WGS) on 19 tumor specimens and analyzed BKPyV integration sites and AA mutational signatures. BKPyV genome integration was detected in 6 of 19 (32%) UC specimens, yielding a total of 21 integration sites. Chromosomes 8 and 12 exhibited higher frequencies of integration events. Among these integration sites, 76% were located within introns, 19% in intergenic regions, and one within an exon. AA mutational signatures were identified in 84% of UC specimens. An APOBEC signature was found in 89% of specimens, with high activity in two specimens from patients with polyomavirus nephropathy. Frequent somatic mutations were observed in genes related to chromatin modification [KMT2C (68%), KMT2D (53%), CREBBP (42%), ARID1A (42%)], cell-cycle regulation [TP53 (58%), NF1 (47%), ATM (32%)], and oncogenic signaling [ERBB2 (21%), PIK3CA (16%), FGFR3 (11%), HRAS (11%)]. Notably, UC specimens with BKPyV integration harbored significantly fewer mutations compared to those with AA mutational signatures. Our findings reveal two distinct molecular subtypes of UC in kidney transplant recipients: one characterized by BKPyV genome integration and the other by AA-associated mutagenesis. These observations suggest divergent mechanisms of UC tumorigenesis and may have implications for diagnosis and treatment in this high-risk population.