Rana McKay, MD, discusses molecular characterization of upper tract vs bladder UC

A recent study found distinct genomic alterations and tumor microenvironment patterns in urothelial carcinoma of the upper tract (UTUC) and bladder (UCB), suggesting a potential avenue to personalize treatment strategies.¹

In a recent interview with Urology Times®, study author Rana R. McKay, MD, FASCO, outlined the background and key takeaways from the study. McKay is a GU medical oncologist at the University of California, San Diego.

For the study, the investigators retrospectively analyzed the somatic, germline, and immunologic landscapes of 505 UTUC and 2416 UCB tumors. Data were collected from the Tempus Database.

Overall, germline variants were present in 4.8% of UCB cases and 5.6% of UTUC tumors. Lynch-syndrome associated gene alterations (MLH1, MSH2, MSH6, PMS2) were present in 0.6% of UCB cases vs 1.8% of UTUC cases (P = .059).

Among all patients, “alterations in TERT, TP53, RB1, ERBB2, and CDKN1A were more frequent in UCB, whereas KMT2D, FGFR3, CDKN2B, KRAS, and MYC were more frequent in UTUC,” the authors wrote.

Further, 17% of UCB cases vs 11% of UTUC cases had a tumor mutational burden of 10 or greater (P < .001). UCB tumors also showed higher PD-L1 positivity, whereas UTUC tumors had more MSI-high (UTUC, 3.2% v UCB, 1%; P = .001) and MMR-deficient (P = .020) cases.

According to the authors, “CD4+ and regulatory T-cell infiltrates were similar in both.”

On next steps for this work, McKay noted, “I think future research is warranted to elucidate the clinical implications of these findings. We don't necessarily have different treatment modalities or different treatment strategies for upper tract vs bladder UC, but that could potentially change.”

REFERENCE

1. Yuen K, Meagher M, Mercer J, et al. Comprehensive comparison of somatic, germline, and immune cell profiles in upper tract and bladder urothelial carcinoma. JCO Precis Oncol. 2025 Aug:9:e2500289. doi:10.1200/PO-25-00289