Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans.
Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans.
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维修辅助损伤检测揭示了非裔美国人和欧洲人之间前列腺癌的生物学差异。
DOI：
10.3390/cancers14041012
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发表时间：
2022-02-17
期刊：
影响因子：
5.2
通讯作者：
Sreekumar A
中科院分区：
文献类型：
--
作者：
Krieger KL;Gohlke JH;Lee KJ;Piyarathna DWB;Castro PD;Jones JA;Ittmann MM;Gassman NR;Sreekumar A
前列腺癌是美国男性中诊断最多的癌症。非裔美国男性被诊断出患有前列腺癌并死于前列腺癌的比率高于其他人口统计群体。之前发表的著作描述了前列腺癌的生物学差异，这种差异可能导致非裔美国人男性的预后比欧洲裔美国人男性更差。这项研究旨在探索在前列腺组织中发现的DNA损伤特征。利用组织芯片，我们发现非裔美国人的前列腺癌比欧美人的前列腺癌有更多的尿嘧啶和嘧啶损伤，UNG水平升高，XRCC1水平降低，这可能表明碱基切除修复途径存在缺陷。此外，这些男性的UMP较高，叶酸循环代谢物的表达较低，这表明代谢重排也可能导致碱基切除修复的失调。非洲裔美国人(AA)被诊断为前列腺癌(PCA)并死于前列腺癌的可能性是欧洲裔美国人(EA)的两倍。越来越多的证据表明，这些肿瘤的生物学差异导致了患者预后的差异。我们的目标是检测AA和EA前列腺组织中DNA损伤的差异。采用修复辅助损伤检测(RADD)方法，对77例AA和EA PCa患者匹配的肿瘤-良性相邻对进行了基本部位、氧化损伤、交联物和尿嘧啶含量的分析。我们的分析表明，总的来说，AA PCA比EA PCA有更多的DNA损伤。AA肿瘤的尿嘧啶和嘧啶损伤增加，而EA肿瘤的氧化损伤更多。AA PCA比EA具有更高的UMP和叶酸循环代谢物水平。尽管尿嘧啶损伤保留在基因组中，AA PCA显示UNG水平高于EA，UNG是尿嘧啶特异性糖基酶。再障患者的碱基切除修复蛋白XRCC1水平也较低。这些结果表明，AA肿瘤的碱基切除修复途径存在功能障碍。此外，这些发现揭示了AA-PCA中的新陈代谢重新连接如何推动生物差异，并为癌症治疗确定了一个有针对性的轴。
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. 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.
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