Murat Akand ^1,2 Tatjana Jatsenko ^3* Tim Muilwijk ^1,2* Thomas Gevaert ^2,4* Steven Joniau ^1,2 Frank Van Der Aa ^1,2*

• ¹ Department of Urology, University Hospitals Leuven, Leuven, Brussels, Belgium
• ² Laboratory of Experimental Urology, Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium
• ³ Laboratory for Cytogenetics and Genome Research, KU Leuven, Leuven, Belgium
• ⁴ Laboratory for Pathological Anatom, AZ Klina, Brasschaat, Belgium

Bladder cancer (BC) is the most common malignancy of the urinary tract. About 75% of all BC patients present with non-muscle-invasive BC (NMIBC), of which up to 70% will recur, and 15% will progress in stage and grade. As the recurrence and progression rates of NMIBC are strongly associated with some clinical and pathological factors, several risk stratification models have been developed to individually predict the short-and long-term risks of disease recurrence and progression. The NMIBC patients are stratified into four risk groups as low-, intermediate-, high-risk, and very high-risk by the European Association of Urology (EAU). Significant heterogeneity in terms of oncological outcomes and prognosis has been observed among NMIBC patients within the same EAU risk group, which has been partly attributed to the intrinsic heterogeneity of BC at the molecular level. Currently, we have a poor understanding of how to distinguish intermediate-and (very-)high-risk NMIBC with poor outcomes from those with a more benign disease course and lack predictive/prognostic tools that can specifically stratify them according to their pathologic and molecular properties. There is an unmet need for developing a more accurate scoring system that considers the treatment they receive after TURBT to enable their better stratification for further follow-up regimens and treatment selection, based also on a better response prediction to the treatment. Based on these facts, by employing a multi-layered -omics (namely, genomics, epigenetics, transcriptomics, proteomics, lipidomics, metabolomics) and immunohistopathology approach, we hypothesize to decipher molecular heterogeneity of intermediateand (very-)high-risk NMIBC and to better stratify the patients with this disease. A combination of different -omics will provide a more detailed and multi-dimensional characterization of the tumor and represent the broad spectrum of NMIBC phenotypes, which will help to decipher the molecular heterogeneity of intermediate-and (very-)high-risk NMIBC. We think that this combinatorial multi-omics approach has the potential to improve the prediction of recurrence and progression with higher precision and to develop a molecular feature-based algorithm for stratifying the patients properly and guiding their therapeutic interventions in a personalized manner.