Abstract 6114: Race-associated base excision repair defects alter the DNA damage landscape in prostate cancer

Prostate cancer is the most diagnosed cancer among men in the United States. African American men are diagnosed with and succumb to prostate cancer at higher rates than other demographic groups. However, the biological drivers contributing to poorer outcomes in African American men compared to European American men with prostate cancer are still poorly defined. One understudied area is DNA repair defects, which drive genomic instability in cancers. Defects in homologous recombination are often at the forefront of repair defects examined and exploited for therapeutic intervention. However, defects in other DNA repair pathways may contribute to poor disease outcomes and chemoresistance. We demonstrated that defects in the base excision repair (BER) pathway contribute to chemoresistance and alter growth in breast cancer. Others have also shown chemoresistant effects from dysregulated BER protein expression in gastric, colorectal, and ovarian cancers. Examination of the TCGA database show dysregulation of key BER protein like X-ray cross complementing protein 1 (XRCC1) and DNA polymerase β (POLβ) are common across several cancers. Therefore, we decided to explore DNA damage and repair defects in prostate cancer to explore if altered DNA repair contributes to poorer outcomes in African American men. To measure DNA repair defects in formalin-fixed paraffin-embedded (FFPE) tissues, we employed a novel assay, Repair Assisted Damage Detection (RADD), which measures DNA lesions within the tissues. RADD fluorescently tags DNA lesions for quantification and is compatible with immunohistochemistry detection of DNA repair or other proteins of interest. Using the tissue microarrays, we used RADD to discover that prostate tumors from African American patients have more uracil and pyrimidine lesions, elevated uracil DNA glycosylase (UNG) levels, and reduced XRCC1 levels than European American tumors, which indicate defects in the BER pathway. In addition, these men had higher uracil monophosphate (UMP) and lower expression of folate cycle metabolites, suggesting that metabolic rewiring may also contribute to the dysregulation of BER. Defects in the BER pathway may offer new therapeutic opportunities for African American prostate cancer patients. These defects may be targeted by therapeutics which pressure the BER pathways. This work demonstrates that functional detection of DNA repair defects through RADD offers new insight into race-specific DNA repair defects offering new molecular targets or therapeutic strategies to reduce racial disparities in prostate cancer. Citation Format: Kaveri Goel, Kimiko Krieger, Manoj Sonavane, Arun Sreekumar, Natalie R. Gassman. Race-associated base excision repair defects alter the DNA damage landscape in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6114.