ERR1-and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans
ERR1-and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans
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DOI：
10.1172/jci127579
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发表时间：
2019-06-03
影响因子：
15.9
通讯作者：
Sreekumar, Arun
中科院分区：
文献类型：
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作者：
Piyarathna, Danthasinghe Waduge Badrajee;Balasubramanian, Akhila;Sreekumar, Arun
背景。与欧洲裔美国患者相比，非洲裔美国患者的癌症死亡率更高，生存时间更短。尽管人们非常关注社会经济因素，但最近的研究结果有力地证明了造成这种差异的生物因素的存在。大多数这些因素都是在癌症类型的特定背景下而不是泛癌背景下描述的。方法。基于基因集富集分析 (GSEA) 与转录因子富集相结合的新型计算机方法，使用癌症基因组图谱数据集来识别泛癌种族差异的常见生物驱动因素。使用多癌组织微阵列方法（TMA）检查患者组织中的线粒体含量。结果。与欧洲裔美国患者的各种癌症类型的肿瘤相比，非洲裔美国患者的肿瘤中线粒体氧化磷酸化独特地丰富。非裔美国患者的肿瘤也表现出 ERR1-PGC1a 介导的转录程序的强烈富集，该程序与线粒体生物发生有关。 TMA 分析显示，与欧洲裔美国患者的相同癌症相比，非洲裔美国患者的癌症含有明显更多的线粒体。结论。这些发现强调了线粒体的变化是泛癌症环境中非裔美国人与欧洲裔美国人患者肿瘤的一个共同区别特征，并为重新利用线粒体抑制剂来治疗非裔美国人患者的癌症提供了理论基础。
BACKGROUND. African American patients have higher cancer mortality rates and shorter survival times compared with European American patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting.METHODS. A novel in silico approach based on Gene Set Enrichment Analysis (GSEA) coupled to transcription factor enrichment was carried out to identify common biological drivers of pan-cancer racial disparity using The Cancer Genome Atlas data set. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA).RESULTS. Mitochondrial oxidative phosphorylation was uniquely enriched in tumors from African American patients compared with tumors of various cancer types from European American patients. Tumors from African American patients also showed strong enrichment for the ERR1-PGC1a-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that cancers from African American patients harbor significantly more mitochondria compared with the same cancers from European American patients.CONCLUSION. These findings highlight changes in mitochondria as a common distinguishing feature among tumors from African American versus European American patients in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat cancers from African American patients.