Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer

Obesity is a high risk factor for colorectal cancer (CRC). The contribution of underlying epigenetic mechanisms to CRC and the precise targets of epigenetic alterations during cancer development are largely unknown. Several types of epigenetic processes have been described, including DNA methylation, histone modification, and microRNA expression. To investigate the relationship between obesity and CRC, we studied both obese and CRC patients, focusing on genome-wide peripheral blood DNA methylation alterations. Our results show abnormal distributions of overlapping differentially methylated regions (DMRs) such as hypermethylated CpG islands, which may account for epigenetic instability driving cancer initiation in obesity patients. Furthermore, functional analysis suggests that altered DNA methylation of extracellular (e.g., O-glycan processing) and intracellular components contribute to activation of oncogenes (e.g. KRAS and SCL2A1) and suppression of tumor suppressors (e.g. ARHGEF4, EPHB2 and SOCS3), leading to increased oncogenic potency. Our study demonstrates how DNA methylation changes in obesity contribute to CRC development, providing direct evidence of an association between obesity and CRC. It also reveals the diagnostic potential of using DNA methylation as an early risk evaluation to detect patients with high risk for CRC.