Simple SummaryRacial disparities in cancer incidence and outcome rates are prevalent in the US, with a variety of contributing factors, such as socioeconomic status, differences in lifestyle, environmental exposures, and biological and genetic determinants. The goal of this research was to broadly analyze public data to identify critical differences in molecular signatures and pathway regulation between races. Additionally, to support the clinical translatability of our work, we evaluated the association of differences in gene expression with patients’ survival outcomes. Our findings help inform the use of novel biomarkers in clinical settings and the future development of race-adjusted precision therapies.AbstractEpidemiological studies reveal disparities in cancer incidence and outcome rates between racial groups in the United States. In our study, we investigated molecular differences between racial groups in 10 carcinoma types. We used publicly available data from The Cancer Genome Atlas to identify patterns of differential gene expression in tumor samples obtained from 4112 White, Black/African American, and Asian patients. We identified race-dependent expression of numerous genes whose mRNA transcript levels were significantly correlated with patients’ survival. Only a small subset of these genes was differentially expressed in multiple carcinomas, including genes involved in cell cycle progression such asCCNB1,CCNE1,CCNE2, andFOXM1. In contrast, most other genes, such as transcriptional factorETS1and apoptotic geneBAK1, were differentially expressed and clinically significant only in specific cancer types. Our analyses also revealed race-dependent, cancer-specific regulation of biological pathways. Importantly, homology-directed repair and ERBB4-mediated nuclear signaling were both upregulated in Black samples compared to White samples in four carcinoma types. This large-scale pan-cancer study refines our understanding of the cancer health disparity and can help inform the use of novel biomarkers in clinical settings and the future development of precision therapies.