MP59-09: Characterizing molecular subtypes of high-risk non-muscle-invasive bladder cancer in african american patients

Sungyong You, Minhyung Kim, Los Angeles, CA, Stephen G. Widen, Alexander Yu, Eduardo J. Eyzaguirre, Galveston, TX, Lars Dyrskjøt, Aarhus N, Denmark, David McConkey, Woonyoung Choi, Baltimore, MD, Dan Theodorescu, Keith S. Chan, Los Angeles, CA, Yong Shan, Douglas S. Tyler, Galveston, TX, Amanda M. De Hoedt, Durham, NC, Stephen J. Freedland*, Los Angeles, CA, Stephen B. Williams, Galveston, TX

Introduction: Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) have heterogeneous outcomes with African Americans (AA) having worse survival than European Americans (EA). It is unknown whether race-based biological differences contribute to this disparity.

Methods: We performed a retrospective cohort study including patients from the University of Texas Medical Branch (UTMB) and the Durham VA Health Care System (DVAHCS) from 2010-2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions of high-risk NMIBC by race were performed using the UROMOL classification system.

Results: A total of 26 patients (14 AA, 12 EA) matched on age and sex were included with no significant difference in clinical stage group (CIS +/- T1 or TaHG vs. TaHG or T1, no CIS), smoking status, or progression. We found a similar racial UROMOL subtype distribution with class 2a being most common. 10 genes were discovered to be commonly upregulated differentially expressed genes (UDEGs) in AA vs EA. EFEMP1, which has been associated with progression to muscle-invasive bladder cancer (MIBC) in vitro, and S100A16 gene expression, which has been implicated with mitomycin C resistance in bladder cancer in vitro, was significantly more common among AA. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which five distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction ability. We mapped the expression of the 10 genes commonly UDEGs by race as a function of the five malignant subtypes. This showed borderline (p=0.056) differences among the subtypes suggesting AA and EA may be expected to have different therapeutic responses to treatments for BC. AA were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EA, yet appeared to have reduced levels of the aggressive C3 bladder tumor cell population.

Conclusions: In this small sample, we found similar subtype distribution among high-risk NMIBC patients according to race. However, gene expression differs by race, supporting potential novel race-based etiologies for differences in muscle-invasion, response to treatments, and transcriptome pathway regulations. Further biological studies in NMIBC molecular sub-stratification, associated treatment(s), and prognoses in a larger cohort are needed to support these hypotheses.

Source of Funding: This study was conducted with the support of a Department of Defense Peer Reviewed Cancer Research Program (PRCRP) Career Development Award (W81XWH1710576), The University of Texas Medical Branch Department of Surgery Seed Grant, the National Institute of Health Loan Repayment Program (SBW), and partially by the National Institutes of Health (NIH) (5TL1TR001440-02) (AY). Opinions expressed in this manuscript are those of the authors and do not constitute official positions of the US Federal Government or the Department of Veterans Affairs.