MOLCARUTUC

Project Coordinator

Joost L. Boormans
- Erasmus MC, Dept. of Urology
- Rotterdam- The Netherlands

Project Partners

Yves Allory
- Institut Curie, Oncologie moléculaire
- Paris - France
Bernardo Herrera
- Virgen de la Victoria University Hospital, Dept. of Urology
- Malaga - Spain
Arndt Hartmann
- University Clinic Erlangen Institute for Pathology
- Erlangen - Germany

Background: 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 draggable 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.

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.

Using two retrospective cohorts of in total 201 UTUC + 53 UCB recurrences (discovery set) and a prospective cohort of 150 UTUC samples (validation set) together with so far 11 UCB recurrences we aim to determine whether:
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

Next generation sequencing of 571 genes, microsatellite instability analysis, and immunohistochemistry are being used to assess TMB, mismatch repair deficiency, immune infiltration and protein-based subtypes.

This project will provide novel insights on the clonality of UTUC and paired UCB. Preliminary data analysis shows a clonal origin in the vast majority of the UTUC and paired UCB. This can be applied to replace cystoscopies by the development of patient-friendly molecular urine assays for surveillance of the bladder after surgery. Moreover, it enables the identification of new actionable genomic alterations of UTUC that serve as targets for therapy, such as precision-guided immunotherapy in UTUC patients with high TMB or FGFR-targeted therapy in UTUC patients with FGFR alterations, leading to durable responses and improved outcome.