Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans

Abstract

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues. Tissue microarrays with matched tumor-benign adjacent pairs from 77 AA and EA PCa patients were analyzed for abasic sites, oxidative lesions, crosslinks, and uracil content using the Repair Assisted Damage Detection (RADD) assay. Our analysis revealed that AA PCa, overall, have more DNA damage than EA PCa. Increased uracil and pyrimidine lesions occurred in AA tumors, while EA tumors had more oxidative lesions. AA PCa have higher levels of UMP and folate cycle metabolites than their EA counterparts. AA PCa showed higher levels of UNG, the uracil-specific glycosylase, than EA, despite uracil lesions being retained within the genome. AA patients also had lower levels of the base excision repair protein XRCC1. These results indicate dysfunction in the base excision repair pathway in AA tumors. Further, these findings reveal how metabolic rewiring in AA PCa drives biological disparities and identifies a targetable axis for cancer therapeutics.

PARP-ish: Gaps in Molecular Understanding and Clinical Trials Targeting PARP Exacerbate Racial Disparities in Prostate Cancer

“…The results of a prostate cancer study showed that XRCC1 protein expression is reduced in AA tumors compared with EA tumors ( P = 0.0005; ref. 51 ) and PARP1 protein expression is similar between tumors of each racial cohort ( P = 0.1562).…”

Single-molecule approaches for DNA damage detection and repair: A focus on Repair Assisted Damage Detection (RADD)

“…RADD offers several advantages over traditional techniques, including high sensitivity, the ability to detect multiple types of damage, and the capacity to study repair dynamics within cells. RADD has been successfully utilized for characterizing DNA damage in fixed cells and tissue sections [44] , [45] , [46] , in global genomic DNA samples at high-throughput [47] , and in DNA sequencing for genomic mapping [48] . Nevertheless, single-molecule detection as summarized in this report holds the highest sensitivity, with access to basal DNA damage levels and the potential of multiplexing with other epigenetic information.…”