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ERR1- and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans
Danthasinghe Waduge Badrajee Piyarathna, … , George Michailidis, Arun Sreekumar
Danthasinghe Waduge Badrajee Piyarathna, … , George Michailidis, Arun Sreekumar
Published June 3, 2019; First published March 28, 2019
Citation Information: J Clin Invest. 2019;129(6):2351-2356. https://doi.org/10.1172/JCI127579.
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Categories: Clinical Medicine Metabolism Oncology

ERR1- and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans

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Abstract

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-PGC1α–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.FUNDING This research was partially supported by National Institutes of Health grants NIH U01 CA167234, NIH 1 U01 CA179674-01A1, 5R01GM11402903, 1U01CA23548701, U01 CA167234, R01CA220297, and R01CA216426; pilot and shared resources support from Dan L. Duncan Cancer Center grant P30 CA125123; and NCI SPORE pilot grant NIH P50 CA186784. It was also partially supported by the Diana Helis Henry Medical Research Foundation; the Brockman Foundation; Agilent Technologies; Department of Defense grants W81XWH-12-1-0130 and W81XWH-12-1-0046; Cancer Prevention Research Institute of Texas grant RP120092; a Prostate Cancer Foundation Challenge Award; National Science Foundation grant DMS-1545277; and American Cancer Society grant 127430-RSG-15-105-01-CNE.

Authors

Danthasinghe Waduge Badrajee Piyarathna, Akhila Balasubramanian, James M. Arnold, Stacy M. Lloyd, Balasubramanyam Karanam, Patricia Castro, Michael M. Ittmann, Nagireddy Putluri, Nora Navone, Jeffrey A. Jones, Wendong Yu, Vlad C. Sandulache, Andrew G. Sikora, George Michailidis, Arun Sreekumar

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Figure 1

Molecular concepts significantly enriched in tumors from self-reported African American patients compared with tumors from European American patients in pan-cancer GSEA analysis.

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Molecular concepts significantly enriched in tumors from self-reported A...
(A) Heatmap showing the top 20 commonly enriched pathways in tumors from African American patients compared with tumors from European American patients, across multiple cancers. See normalized enrichment score (NES) scale on the top. All GSEA concepts listed are significant at FDR < 0.25. (B) Table showing the individual NES for the 3 top commonly enriched pathways for each cancer type (FDR < 0.05). (C) Heatmap showing enrichment of OXPHOS in 5 independent cancer data sets. (D) Table showing individual NES for the 5 independent data sets. Columns represent cancer type, and rows represent the enriched concepts. Shades of red and blue describe positive and negative enrichment scores, respectively. LAML, acute myeloid leukemia; STAD, stomach adenocarcinoma; SARC, sarcoma; HNSC, head and neck squamous cell carcinoma; KIRC, kidney renal clear cell carcinoma; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; LIHC, live hepatocellular carcinoma; KIRP, kidney renal papillary cell carcinoma; PRAD, prostate adenocarcinoma; KICH, kidney chromophobe; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; GBM, glioblastoma multiforme; BLCA, bladder cancer; KIPAN, pan-kidney cohort; COAD, colon adenocarcinoma; OV, ovarian adenocarcinoma; BRCA, breast cancer; LGG, brain low grade glioma; GBMLGG, glioblastoma multiforme low grade glioma; UCEC, uterine corpus endometrial carcinoma; PCPG, pheochromocytoma and paraganglioma; THCA, thyroid carcinoma; PCa, prostate cancer.
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