Agilent Posters at ASMS 2017

Racial Disparity in Bladder Cancer: Altered Metabolism in African-Americans Compared to European-Americans

Importance of the topic

Bladder cancer incidence, mortality, and clinical outcomes differ significantly across racial groups, with African-Americans (AA) exhibiting poorer survival despite lower incidence than European-Americans (EA). Metabolic reprogramming is a hallmark of cancer and may drive these disparities. A deeper understanding of tumor metabolism in AA versus EA bladder cancer could inform precision medicine approaches and reduce outcome gaps.

Objectives and study overview

This study aimed to identify metabolic differences in tumor tissues from AA and EA bladder cancer patients. We performed targeted metabolomics of over 200 endogenous metabolites using LC–MS/MS and a Biocrates AbsoluteIDQ p180 Kit. Complementary molecular assays (qPCR, western blot) validated key enzyme expression changes in cell lines and patient tissues.

Methodology and instrumentation used

• Sample cohorts: 15 AA and 20 EA bladder cancer tissue samples.
• Targeted metabolomics: Agilent 6495 Triple Quadrupole LC/MS with electrospray ionization, employing positive and negative modes.
• Quantification: Biocrates p180 Kit, 10 µL plasma equivalents, internal standards for normalization.
• Data analysis: Agilent MassHunter software.
• Molecular validation: J82 (EA) and ScaBER (AA) cell lines; qPCR and western blot assessed GLS1, IDH2, ADHFE1, NAT8L, ASPA, PLA1A, LRAT expression.

Main results and discussion

• Mitochondrial metabolites: D-2-hydroxyglutarate (D-2HG), N-acetylaspartate (NAA), and glutamine were significantly elevated in AA bladder tumors.
• Enzymes: GLS1, IDH2, and ADHFE1 (drivers of D-2HG synthesis) showed higher mRNA and protein levels in AA versus EA tumors. NAT8L (NAA synthesis) was upregulated, while ASPA (NAA catabolism) was downregulated in AA tissues.
• Lipid metabolism: Lysophosphatidylcholines (LPC) were increased, whereas phosphatidylcholines (PC) decreased in AA tumors. Enzymes PLA1A and LRAT, which convert PC to LPC, were overexpressed in AA tumors.
• These findings suggest enhanced anaplerotic flux into the tricarboxylic acid cycle, accumulation of oncometabolites (D-2HG, NAA), and dysregulated phospholipid remodeling in AA bladder cancer.

Benefits and practical applications

• Identification of race-associated metabolic signatures may guide development of biomarkers for risk stratification and personalized therapy.
• Key metabolic enzymes (GLS1, IDH2, ADHFE1, NAT8L, PLA1A, LRAT) represent potential therapeutic targets or companion diagnostics tailored to AA patients.

Future trends and applications

• Broader metabolomic profiling across multi-ethnic cohorts to validate and refine racial disparity biomarkers.
• Integration of metabolomics with genomics and epigenomics for comprehensive mapping of molecular disparities.
• Preclinical testing of inhibitors targeting GLS1 or IDH2 in AA-derived bladder cancer models.

Conclusion

This study uncovers pronounced alterations in mitochondrial and phospholipid metabolism in AA versus EA bladder cancer, driven by differential expression of key metabolic enzymes. Such race-specific metabolic rewiring may underlie clinical disparities and offers avenues for personalized interventions.

References

1. Urology. 2011 Sep;78(3):544–549. doi:10.1016/j.urology.2011.02.042
2. Clinical Cancer Research. 2016 Oct 19. doi:10.1158/1078-0432.CCR-16-1647