Interrogating the Mechanistic Link between Neighborhood Deprivation and Colorectal Cancer Risk through Transcriptomic Analysis of Normal Colorectal Biopsies

BACKGROUND: Greater neighborhood deprivation, as defined by the Neighborhood Deprivation Index (NDI), has been associated with increased colorectal cancer (CRC) risk. However, the biological mechanisms underlying this association remain unclear. METHODS: Normal colorectal biopsies (matched right and left colon, and rectum) from African Americans (AA; (n = 34)) and European Americans (EA; (n = 23)) adults undergoing colonoscopy were collected for a cross-sectional study in Cleveland, Ohio. NDI-associated differentially expressed genes (DEGs) were identified from RNA-sequencing (RNA-seq) using limma. Normal colon organoid lines were derived from biopsies of AA (n = 4) and EA (n = 6) individuals in Charlottesville, Virginia, treated daily with metformin for 72-hours, and metformin-DEGs were identified in limma. RESULTS: A total of 237 DEGs were found to be commonly associated with NDI in AA and EA populations across individual-matched biopsy triplets (right and left colon, and rectum). Of the 237 NDI-associated DEGs, 82 overlapped with CRC tumor DEGs from a publicly available dataset (P=2.21E⁻05), and nine were prioritized as therapeutic targets, including MYC overexpression (Benjamani Hochberg (BH)=2.48E-12). Metformin exposure in colon organoids also altered the expression of 28 of these genes, with ~79% showing opposite direction, including reduced MYC expression (BH=0.095). CONCLUSIONS: NDI is associated with CRC-related transcriptional differences. The observed reversal of gene expression by metformin, including at MYC, suggests a potential role for metformin in reducing CRC risk by modifying NDI-high related gene expression. IMPACT: NDI-associated CRC risk genes provide novel opportunity for future biomarkers or early therapeutic targets in at-risk populations.