Interrogating the mechanistic link between neighborhood deprivation and colorectal cancer risk through gene expression analysis of normal colorectal biopsies

Importance: Neighborhood socioeconomic status has been associated with increased colorectal cancer (CRC) risk, particularly among different racial groups, yet the biological mechanisms underlying this association remain unclear. Objective: To investigate whether neighborhood deprivation, as assessed by Neighborhood Deprivation Index (NDI), is associated with differential gene expression in normal colorectal biopsies; to explore molecular links to CRC risk and to identify potential chemoprevention targets. Design: A cross-sectional study involving transcriptomic analysis of normal colorectal tissues and meta-analysis of gene expression data between African Americans (AA) and European Americans (EA), and an experimental study exposing colon organoids derived from healthy colon biopsies to metformin. Setting: Participants were enrolled in the Cleveland Colon Screening and Risk Factors Study (2012-2018) in metropolitan Cleveland, Ohio. Organoids were derived from colon biopsies of patients undergoing colonoscopy in Charlottesville, Virginia. Participants: Normal colorectal biopsies from AA (n = 34) and EA (n = 23) adults undergoing colonoscopy were analyzed. Colon organoids were derived from AA (n = 4) and EA (n = 6) individuals. RNA-seq data was generated from each participant. Main Outcome(s) and Measures: Differentially expressed genes (DEGs) associated with NDI in normal colorectal biopsies and overlap with DEGs identified in CRC tumor tissues; and association of metformin on NDI-associated, CRC risk gene expression. Results: A total of 237 DEGs were found to be commonly associated with NDI across individual-matched biopsy triplets (right and left colon, and rectum) in both racial groups. Cellular metabolism pathways were amongst the most significantly enriched within identified DEGs. Of the 237 NDI associated DEGs, 82 overlapped with CRC tumor DEGs from a publicly available dataset (TCGA-COADREAD; P=2.21×10⁻⁵; OR=1.83), and nine were prioritized as therapeutic targets, including MYC overexpression (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). Conclusion and Relevance: NDI is associated with CRC-related transcriptional differences. These findings suggest potential molecular mechanisms linking neighborhood deprivation to CRC risk. The observed reversal of gene expression by metformin suggests a potential role for metformin in reducing CRC risk in high NDI-populations, who face greater than average risk of developing CRC.