Project Summary Esophageal cancer is one of the most aggressive forms of human malignancy. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the primary histological subtypes of esophageal cancer. Clear race-based disparities exist with regard to incidence of esophageal cancer in the US with EAC most often affecting Caucasian ancestry men (CA) and ESCC primarily occurring in African American/Black (AA/B) men. Moreover, esophageal cancer collectively is more deadly in AA/B patients as compared to their CA counterparts. Currently, our understanding of the biological underpinnings of the described racial disparities in esophageal cancer remains limited. In the current proposal we will directly perform scRNA-Seq on esophageal biopsy specimens from esophageal mucosa of AA/B and CA subjects to test the innovative hypothesis that race- associated alterations in the molecular and cellular heterogeneity of esophageal mucosa contribute to disparities in esophageal cancer incidence. In Aim 1, we will interrogate tissues from AA/B and CA healthy controls with normal esophageal pathology. In Aim 2, we will interrogate adjacent normal tissue from human subjects with esophageal tumors. This study represents the first evaluation of race-based differences in esophageal mucosa at the level of single cell resolution. It will also be the first study to examine this cellular heterogeneity in both healthy and esophageal cancer patients. To successfully reach this goal, the proposed studies leverage (1) the diverse patient population at TUH; (2) the PIs established pipeline for esophageal biopsy procurement and expertise in esophageal pathophysiology; and (3) the collaborators respective expertise in esophageal cancer (Dr. Whelan), clinical and translational esophageal research (Dr. Reichenbach), bioinformatics analysis of large- scale genomics data (Karami), and health disparities (Dr. Ma). Identification of cell types and pathways displaying differential representation or expression in AA/B and CA subjects has great potential to inform our understanding of the biological underpinnings of established racial disparities in esophageal cancer incidence.