Danthasinghe Waduge Badrajee Piyarathna1,2, Akhila Balasubramanian1,2,3, James M Arnold1,2, Stacy M Lloyd1,2, Balasubramanyam Karanam4, Patricia Castro5,6, Michael M Ittmann5,6, Nagireddy Putluri1,2, Nora Navone7, Jeffrey A Jones8, Wendong Yu5, Vlad C Sandulache9, Andrew G Sikora9, George Michailidis10, Arun Sreekumar1,2,3. 1. Department of Molecular and Cellular Biology. 2. Alkek Center for Molecular Discovery, and. 3. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA. 4. Department of Biology and Cancer Research, Tuskegee University, Tuskegee, Alabama, USA. 5. Department of Pathology and. 6. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA. 7. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 8. Michael E. DeBakey Veteran Affairs Medical Center and Department of Urology and. 9. Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA. 10. Department of Statistics, University of Florida, Gainesville, Florida, USA.
Abstract
BACKGROUND: African American (AA) patients have higher cancer mortality rates and shorter survival times compared to European American (EA) 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 (TCGA) dataset. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA). RESULTS: Mitochondrial oxidative phosphorylation was uniquely enriched in AA tumors compared to EA tumors across various cancer types. AA tumors also showed strong enrichment for the ERR1-PGC1α-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that AA cancers harbor significantly more mitochondria compared to their EA counterparts. CONCLUSIONS: These findings highlight changes in mitochondria as a common distinguishing feature between AA and EA tumors in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat AA cancers.
BACKGROUND: African American (AA) patients have higher cancer mortality rates and shorter survival times compared to European American (EA) 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 (TCGA) dataset. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA). RESULTS: Mitochondrial oxidative phosphorylation was uniquely enriched in AA tumors compared to EA tumors across various cancer types. AA tumors also showed strong enrichment for the ERR1-PGC1α-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that AA cancers harbor significantly more mitochondria compared to their EA counterparts. CONCLUSIONS: These findings highlight changes in mitochondria as a common distinguishing feature between AA and EA tumors in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat AA cancers.
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