On a population level, African-Americans (AAs) with bladder cancer have been found to have an up to 2-fold increased risk of bladder cancer specific death compared to Caucasians. Between 1975 and 2005, African-Americans have persistently had worse bladder cancer specific survival than any other racial group. While socioeconomic and access-to-care differences according to race have been identified in bladder cancer, it is unknown whether biological differences and data from clinical trials applied across race groups also contribute to this disparity in outcomes.
The vast majority (~70%) of new BC cases are non-muscle invasive BC (NMIBC) that often have an indolent disease course. High-risk NMIBC may progress in 33% of patients at 10 years. Consequently, identifying those at the highest risk of progression to muscle-invasive BC (MIBC) is a major unmet clinical need.
Leveraging an expert team of developers of the bladder cancer subtype classification systems, bioinformatics, and health services researchers, we sought to determine whether differences in subtype distribution and differentially expressed genes exist between AAs and European Americans (EAs) in patients with high-risk NMIBC. Patients with high-risk NMIBC were identified at the University of Texas Medical Branch (UTMB) Health system and the Durham Veterans Affair Health Care System (DVAHCS) from January 1, 2010, to December 31, 2020. These patients were stratified by gender (male/female), and we performed a greedy algorithm matching patient age between the AA and EA cohorts at each institution. The final study population consisted of a total of 26 patients (14 AAs and 12 EAs) matched on age and sex. Normalized profiled gene expressions of high-risk NMIBC by race were performed and applied to UROMOL classification using the UROMOL classifier. Racial differences in transcriptomic pathways were evaluated with gene set enrichment analysis (GSEA). We used single nuclei analysis to map the malignant cell heterogeneity and mapped the expression of the 10 genes commonly upregulated from both cohorts.
The UROMOL subtype classification revealed a high prevalence of the class 2a subtype in both race groups. A total of 201 genes and 290 genes were discovered to be significantly differentially expressed in the UTMB and DVAHCS cohorts, respectively. 10 genes were discovered to be commonly upregulated in AAs compared to EAs from both cohorts and AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs. Mapping of the expression of the 10 genes commonly upregulated from both cohorts as a function of the five malignant subtypes showed borderline (p=0.056) differences among the subtypes, with AAs demonstrating reduced expression of genes associated with the recently described C3 (Cell-Cell-Communication, CDH12/N-Cadherin 2) subtype.
While hypothesis generating and small numbers, our findings support 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 underway to support these hypotheses.
Written by: Stephen B. Williams, MD, MBA, MS, FACS, Medical Director for High Value Care, UTMB Health System, Chief, Division of Urology, Professor (Tenured), Urology and Radiology, The Robert Earl Cone Professorship, Director of Urologic Oncology, Director of Urologic Research, Co-Director, UTMB Surgical Outcomes Research Program, The University of Texas Medical Branch