TY - JOUR
T1 - ERR1- And PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans
AU - Piyarathna, Danthasinghe Waduge Badrajee
AU - Balasubramanian, Akhila
AU - Arnold, James M.
AU - Lloyd, Stacy M.
AU - Karanam, Balasubramanyam
AU - Castro, Patricia
AU - Ittmann, Michael M.
AU - Putluri, Nagireddy
AU - Navone, Nora
AU - Jones, Jeffrey A.
AU - Yu, Wendong
AU - Sandulache, Vlad C.
AU - Sikora, Andrew G.
AU - Michailidis, George
AU - Sreekumar, Arun
N1 - Publisher Copyright:
Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019/6/3
Y1 - 2019/6/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI127579
DO - 10.1172/JCI127579
M3 - Article
C2 - 30920960
AN - SCOPUS:85064127143
SN - 0021-9738
VL - 129
SP - 2351
EP - 2356
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -