Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study.

Background: An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African-American (AA) adults consume greater quantities of fructose and are more likely to develop right-side colon cancer than European American (EA) adults.

Objectives: We examined the hypothesis that fructose consumption leads to epigenomic and transcriptomic differences associated with CRC tumor biology.

Methods: Deoxyribonucleic acid methylation data from this cross-sectional study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of Food Frequency Questionnaire data on fructose consumption in normal colon biopsies (n = 79) of AA adults undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from The Cancer Genome Atlas Colon Adenocarcinoma, GSE101764, and GSE193535. Right colon organoids derived from AA (n = 5) and EA (n = 5) adults were exposed to 4.4 mM of fructose for 72 h. Differentially expressed genes (DEGs) were identified using DESeq2.

Results: We identified 4263 right colon fructose-associated DMRs [false-discovery rates (FDR) < 0.05]. In contrast, only 24 DMRs survived multiple testing corrections (FDR < 0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in ≥1 of 3 data sets. Highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in right colon organoids of AA individuals (P = 3.28E^-30). Overlapping and significant enrichments for fatty acid metabolism, glycolysis, and cell proliferation pathways were also found. Cross-referencing genes within these pathways to DEGs in CRC tumors reveal potential roles for ankyrin repeat domain containing protein 23 and phosphofructokinase, platelet in fructose-mediated CRC risk for AA individuals.

Conclusions: Our data support that dietary fructose exerts a greater CRC risk-related effect in the right than left colon among AA adults, alluding to its potential role in contributing to racial disparities in CRC.