Comprehensive Comparison of Somatic, Germline, and Immune Cell Profiles in Upper Tract and Bladder Urothelial Carcinoma

PURPOSE Molecular characterization of anatomically distinct urothelial carcinoma in the upper tract (UTUC) and bladder (UCB) has been challenging because of the rarity of UTUC. However, recent advances in real-world data curation have facilitated the generation of larger UTUC cohorts. In this study, we investigated the somatic, germline, and immunologic landscapes of UTUC compared with UCB. METHODS From the Tempus Database, we retrospectively analyzed 505 UTUC and 2,416 UCB cases. Tumors were sequenced using Tempus xT DNA and xR RNA assays. Pathogenic somatic mutations, immune cell infiltration, tumor mutational burden (TMB), PD-L1, microsatellite instability (MSI), and mismatch repair (MMR) were evaluated. Potential germline alterations were assessed in 46 genes for patients with tumor/normal matched sequencing (UTUC, n = 285; UCB, n = 1,359). RESULTS 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. Germline variants were found in 4.8% of UCB and 5.6% of UTUC, with trends toward higher Lynch syndrome–associated gene alterations ( MLH1, MSH2, MSH6, PMS2 ) in UTUC (0.6% v 1.8%, P = .059). The prevalence of TMB ≥10 mut/Mb was higher in UCB (17% v 11%, P < .001). UCB had higher PD-L1 positivity ( P = .013), whereas UTUC had more MSI-high (UTUC = 3.2% v UCB = 1%, P = .001) and MMR-deficient ( P = .020) cases. CD4 + and regulatory T-cell infiltrates were similar in both. CONCLUSION By comprehensive molecular characterization of UC, we observed distinct genomic alterations and tumor microenvironment patterns in UTUC and UCB. Further research is warranted to elucidate the clinical implications of these findings. We compared the genetic and immune features of upper tract and bladder cancers. Our study found key differences that could affect treatment decisions, such as specific gene changes and immune markers. These insights may help doctors personalize therapies and improve patient care.