Dear editors,

Solid organ transplant recipients face a substantially elevated risk of post-transplant malignancies due to lifelong immunosuppression and impaired viral immune surveillance [1]. While most post-transplant tumors are de novo, donor-derived tumors (DDTs) represent a rare, highly informative biological model arising from engrafted donor-derived cells that behave as tumor-initiating cells (TICs) within the recipient host [2, 3]. Here, we report a unique case of donor-derived high-grade urothelial carcinoma originating in a two-time kidney transplant recipient with chronic JC polyomavirus (JCPyV) infection, highlighting a complex interplay between chronic viral inflammation, persistent immunosuppression, and donor-cell somatic mutation [4, 5].

A 59-year-old male with end-stage renal disease initially received a kidney transplant from a deceased male donor (karyotype XY) in 2006. Seven years post-transplantation, he developed JCPyV-associated nephropathy, leading to graft failure. In 2021, he received a second kidney transplant from a deceased female donor (karyotype XX). Despite immunosuppressive adjustment with everolimus, JCPyV replication persisted at high levels in plasma, urine, and cerebrospinal fluid. Two years after the second transplant, the patient presented with macrohematuria. Work-up revealed a high-grade invasive urothelial carcinoma of the bladder involving the left ureteral orifice, requiring bilateral native and graft nephroureterectomy with radical cystectomy. To elucidate the cellular origin and oncogenic drivers of the lesion, six fresh tissue specimens were collected from native and transplanted structures. Multiplex QF-PCR short tandem repeat (STR) analysis (Elucigene QST*Rplusv2) and in vitro primary tissue culture in Chang medium were conducted. Targeted Next-Generation Sequencing (NGS) covering 67 cancer-related genes (Archer VariantPlex Solid Tumor Kit) was performed on both the neoplastic lesion and macroscopically normal tissues (Figure 1).

STR profiling revealed that non-neoplastic native tissues (native bladder and native ureters) shared an identical recipient haplotype (XY). In contrast, the left transplanted ureter and the hyperemic bladder carcinoma displayed a distinct XX donor genotype, interspersed with recipient-derived allelic peaks indicative of local cellular chimerism. Primary cells isolated from the hyperemic bladder area and the left transplanted ureter were successfully expanded over five passages in culture, acquiring an immortalized phenotype with a homogeneous XX donor karyotype.

Targeted NGS identified a specific PIK3CA mutation (c.1571G>A, p.Arg524Lys) in both the hyperemic bladder carcinoma and the macroscopically normal left transplanted ureter. No other pathogenic variants were detected across the 67-gene panel. Real-time PCR confirmed JCPyV DNA persistence across all tissue specimens (range: 3.2 × 104 to 1.1 × 105 copies/mL), although viral DNA was absent in the expanded in vitro cellular pellets, excluding direct ongoing viral integration within the cultured neoplastic clone.

The concordant STR profiles obtained from tumor tissue and cultured cells, together with the clonal expansion of XX cells in vitro and the detection of the same PIK3CA mutation in both ureteral and bladder lesions, strongly support a donor-derived origin of the tumor-initiating cells rather than a secondary infiltration or mosaic event. Rather than a late passenger event, this PIK3CA substitution—located within the helical domain of the PI3K/AKT/mTOR pathway—appears to represent an early somatic alteration present in engrafted donor cells [6, 7]. We hypothesize a model wherein donor-derived TICs harboring the PIK3CA variant migrated from the transplanted ureter to the bladder mucosa.

Importantly, JCPyV likely contributed to tumor development indirectly via a “field effect” mechanism [8]. Chronic viral infection induced localized, severe chronic cystitis, establishing an inflamed microenvironment. Synergizing with systemic immunosuppression, this permissive inflammatory niche favored the engraftment, survival, and subsequent clonal expansion of donor-derived TICs.

This case is more than a rare oncologic curiosity—it provides a living model of early carcinogenesis. In a scenario where donor and recipient cells are genomically distinguishable, chimerism could enable the tracking of tumor initiation from its earliest steps, allowing the isolation of the first altered cells, those that silently pave the way for clinical cancer long before dysplasia becomes evident.

Current sequencing efforts focus largely on late-stage tumors, where all cancer cells share the same set of “public mutations,” masking the founding event of transformation. Here, we had the rare opportunity to detect that founding event in a context where the neoplastic population emerged from a known origin and timeline, offering an unparalleled view of tumor initiation in vivo.

This case demonstrates that molecular chimerism analysis combined with targeted genomic profiling of non-neoplastic tissues can track the earliest stages of donor-derived oncogenesis in vivo. Extending genomic surveillance beyond traditional clinical timelines may improve cancer risk stratification and early detection in solid organ transplant recipients [9,10].