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

Kimiko L Krieger,Kevin J Lee,Michael M Ittmann,Danthasinghe Waduge Badrajee Piyarathna,Patricia D Castro,Jie H Gohlke,Jeffrey A Jones,Arun Sreekumar,Natalie R Gassman

doi:10.3390/cancers14041012

Abstract

Simple SummaryProstate 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. Previously published works described the biological differences in prostate tumors that may contribute to poorer outcomes in African American men compared to European American men. This study was designed to explore the DNA lesion profiles found in prostate tissues. Using tissue microarrays, we found that prostate tumors from African American patients have more uracil and pyrimidine damage, elevated UNG levels, and reduced XRCC1 levels than European American tumors, which may indicate defects in the base excision repair pathway. In addition, these men had higher UMP and lower expression of folate cycle metabolites, suggesting that metabolic rewiring may also contribute to the dysregulation of base excision repair.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.

Highlights

Prostate cancer (PCa) is the most diagnosed cancer among men in the United States [1].African American (AA) men are two times more likely to be diagnosed with and succumb to prostate cancer than European Americans (EA) [1]
We applied the full Repair Assisted Damage Detection (RADD) assay to these arrays to measure abasic sites, alkylation and oxidative lesions, pyrimidine crosslinks, uracils, and strand breaks [15]
The Full RADD cocktail is composed of the bacterial repair enzymes Uracil DNA glycosylase (UDG), recognizing uracil lesions; Fapy-DNA glycosylase (FPG), oxidative lesions; T4 pyrimidine dimer glycosylase (T4 PDG), pyrimidine crosslinks; 3-alkyladenine DNA glycosylase (AAG), alkylating lesions; and Endonuclease

Summary

Introduction

Prostate cancer (PCa) is the most diagnosed cancer among men in the United States [1].African American (AA) men are two times more likely to be diagnosed with and succumb to prostate cancer than European Americans (EA) [1]. Prostate cancer (PCa) is the most diagnosed cancer among men in the United States [1]. Our lab previously identified DNA repair as a top gene signature enriched in AA compared to EA across a pan-cancer gene set enrichment analysis (GSEA) of TCGA data [13]. We found this signature enriched in 22 out of 28 cancer gene sets, including PCa [13]. This study explored DNA repair and genomic instability differences between AA and EA PCa patients

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