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Published on: April 29, 2014
Interrogating the Mechanistic Link between Neighborhood Deprivation and Colorectal Cancer Risk through Transcriptomic
Matthew A Devall1,2, Hania M Taha1, Mackenzie Chen1
1Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
Background:
Greater neighborhood deprivation, as defined by the neighborhood deprivation index (NDI), has been associated with increased colorectal cancer risk. However, the biological mechanisms underlying this association remain unclear.
Methods:
Normal colorectal biopsies (matched right and left colon and rectum) from African American [AA (n = 34)] and European American [EA (n = 23)] adults undergoing colonoscopy were collected for a cross-sectional study in Cleveland, Ohio. NDI-associated differentially expressed genes (DEG) were identified from RNA sequencing 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 colorectal cancer tumor DEGs from a publicly available dataset (P = 2.21E-05), and 9 were prioritized as therapeutic targets, including MYC overexpression [Benjamini-Hochberg (BH) = 2.48E-12]. Metformin exposure in colon organoids also altered the expression of 28 of these genes, with ∼79% showing the opposite direction, including reduced MYC expression (BH = 0.095).
Conclusions:
NDI is associated with colorectal cancer-related transcriptional differences. The observed reversal of gene expression by metformin, including at MYC, suggests a potential role for metformin in reducing colorectal cancer risk by modifying NDI-high related gene expression.
Impact:
NDI-associated colorectal cancer risk genes provide a novel opportunity for future biomarkers or early therapeutic targets in at-risk populations.
