While the reported worldwide age-standardized incidence rate (ASR) for esophageal cancer (EC) is 9.0 cases per 100,000 population per year, this rate does not reflect wide geographic variations in incidence. Currently, more than 80% of cases and deaths from EC occur within developing countries. One of the most striking features of EC is the presence of defined high-incidence geographic regions, including locales in northern China, northeastern Iran, eastern South America, and South Africa. Our group previously reported eastern Africa as another geographic “hot spot” with disproportionately high ASRs ranging from 22.6 to 47.2 per 100,000 males in four urban centers. This project aims to utilize biospecimens obtained from patients with EC to evaluate possible genetic, molecular, and infectious determinants of this high-incidence disease in Tanzania. Aim 1: To survey the transcriptome of EC tumor specimens for pathogen-encoded RNA and sensitive viral motif recognition bio-informatic analysis. Aim 2: To evaluate the somatic mutational rate, mutational pattern, copy number profiles, and recurrently mutated genes in tumor specimens obtained from EC patients in Tanzania. By attempting to define the underlying molecular etiology of EC, this project may impact strategies for EC prevention efforts in Tanzania and other high-incidence areas of East Africa.