Assessment of colorectal cancer risk factors through the application of network-based approaches in a biracial cohort of colon organoid stem cells

Numerous demographic factors have been associated with colorectal cancer (CRC) risk, with age, body mass index, smoking history, sex, and differences in ancestry, among the most consistent. However, biological mechanisms underlying these associations remain unclear. Limitations of traditional cancer models, such as animal models and CRC cell lines, and the large data dispari-ty between European American and minority groups present challenges in relating mechanisms to the average-risk population. There is a need for studies to be performed in a racially diverse pop-ulations and in cells relevant to CRC initiation. Colon crypt stem cells are believed to be the pri-mary cells of origin for CRCs. In this study, we enriched for stem cell populations in organoids derived from the healthy colon of seven European Americans and eight African Americans. Weighted gene co-expression network analysis was performed following RNA sequencing to identify modules of gene co-expression that were differentially associated with these five CRC risk factors. Candidate driver genes of CRC risk were identified through analysis of module structure and overlaid with data derived from publicly available CRC tumors and genome-wide association studies. We identified several genes that represent putative targets of CRC risk factors and warrant further investigation Overall design: RNA-sequencing protocols were performed on healthy African American and European American stem cell enriched colon organoids derived from right colon at the time of colonoscopy.