Clonal evolution and molecular stratification of urothelial carcinoma in situ of the urinary bladder

• Applicant: Professorin Dr. Nadine Gaisa, since 5/2023
• Subject Area: Pathology ; Reproductive Medicine, Urology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418056052

Bladder cancer is a heterogeneous disease with divergent clinical and oncological courses. Urothelial carcinoma in situ (CIS) is the aggressive pre-invasive intraurothelial lesion, from which the majority of muscle-invasive bladder carcinomas with poor prognosis arises. So far, neither the molecular evolution of CIS is sufficiently understood, nor is it possible to predict which CIS patients will have stable disease that can be treated with conservative intravesical instillation therapy, and which patient group will progress and might benefit from undergoing early cystectomy. Furthermore, first-line therapy, i.e. intravesical instillation of bacillus Calmette-Guérin (BCG), fails in more than 50 % of cases due to toxicity or treatment resistance, and second-line therapy radical cystectomy results in possible overtreatment and causes drastic lifestyle consequences. Therefore, in this proposal we aim to decipher the genetic landscape of urothelial CIS by performing a multiregional whole exome sequencing approach, initially on cryopreserved, completely embedded cystectomy specimens containing CIS. We will use bioinformatics to analyse clonal heterogeneity and evolution of CIS in order to understand the basic disease development and its dynamics, and to deduce prognostically relevant information for therapeutic stratification as well as to identify genetic events which hold promise for effective targeted therapy. Potentially druggable CIS alterations will be assessed functionally in in vitro models for their putative predictive and therapeutic impact. Based on the assumption that a more diverse tumour is able to adapt more efficiently to changing environmental conditions resulting in faster tumour growth and progression, we aim to determine the suitability of inter-patient within-CIS genetic diversity measures as a robust criterion for independent prognostic stratification (intravesical therapy versus radical cystectomy). Prospectively (in subsequent projects), we aim to validate the basic results from this project for CIS risk stratification in longitudinal biopsy cohorts, that we are currently establishing.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Stefan Garczyk, until 5/2023