Upper urinary tract urothelial carcinoma (UTUC) patients have poor outcomes and a high risk of future urothelial carcinoma of the bladder (UCB) after radical surgery. Currently, diagnostic tools that predict the risk of a UCB recurrence are lacking and more effective therapies are needed to improve survival. This project envisions the identification of novel genetic leads for improved diagnostics and therapy by large-scale genomic characterization of UTUC and paired UCB recurrences as the solution to address these clinical needs. Hypothesis: 1) UTUC and UCB recurrences are clonally related, enabling surveillance by molecular urine diagnostics 2) UTUC is characterized by molecular alterations that lead to high tumor mutational burden (TMB), offering a target for immunotherapy Aims: Primary: to clarify the clonal origin of UTUC and paired UCB recurrences Secondary: to identify genomic alterations of UTUC and to investigate the potential of these aberrations as novel druggable targets and predictors of response to therapy Methods: A retrospective cohort of 199 UTUC + 99 UCB recurrences (discovery set) and a prospective cohort of 170 UTUC samples (validation set) are compiled. Whole exome sequencing, microsatellite instability analysis, and immunohistochemistry are done to assess TMB, mismatch repair deficiency, immune infiltration and molecular subtypes. The genomic profile of UTUC and paired UCB is compared and molecular alterations of UTUC are correlated with clinical outcome and therapy response.
Expected results and potential impact: This project provides novel insights on the clonality of UTUC and paired UCB. This can be applied to replace cystoscopies by patient-friendly urine assays for surveillance after surgery. Moreover, it enables the identification of new actionable genomic changes of UTUC that serve as targets for therapy, such as precision-guided immunotherapy in UTUC patients with high TMB leading to durable responses and improved outcome.