Strategy to Analyze Urine Tumor DNA Predicts Outcomes in Bladder Cancer

Analysis of urine tumor DNA (utDNA) holds great promise as a tool to monitor non–muscle-invasive bladder cancer (NMIBC). However, the presence of mutant DNA from normal urothelium, which arises in a phenomenon termed field cancerization, limits the specificity of such analyses. Additionally, previous studies have not distinguished biomarkers of response to surgery versus adjuvant Bacillus Calmette-Guerin (BCG) therapy, which are both used for treatment of intermediate- and high-risk tumors. In this study, Shi, Liu, and colleagues developed a novel approach that combines urine cancer personalized profiling by deep sequencing (uCAPP-seq) with a statistical approach that removes field effect mutations, called RePhyNERX (“refiner X”), to increase the specificity of utDNA analysis for disease monitoring. In patients without bladder cancer, uCAPP-seq analysis revealed the incidence of putative oncogenic mutations in PLEKHS1, TERT, KMT2D, and FGFR3 that increased with age, a phenomenon they termed “clonal cystopoiesis” given its parallels with clonal hematopoiesis. Using RePhyNERX-enhanced uCAPP-seq, mutations arising from bladder cancers were detected in urine from patients with NMIBC, and utDNA concentrations were found to associate with distinct treatment responses and outcomes. While presurgical utDNA levels did not correlate with recurrence or survival, detection of utDNA following surgery or subsequent BCG induction increasingly associated with recurrence. BCG responders, identified based on utDNA decrease after treatment, were characterized by higher tumor mutation burden and enhanced immune signaling compared to non-responders. Moreover, a positive T cell–to-stroma enrichment (TSE) score signified an increased likelihood of response to BCG. Finally, urine displayed increased abundance of bladder cancer DNA compared to plasma in patients with NMIBC, suggesting the high potential clinical relevance of the method in this clinical setting. Altogether, this study details the development and validation of a novel approach to utDNA analysis that can aid in treatment selection, response evaluation, and possibly the management of additional cancer types.Shi WY, Liu KJ, Esfahani MS, Mach KE, Phillips NA, Almanza D, et al. Field-effect-informed urine liquid biopsy for bladder cancer. Cell 2026 Jan 27 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.