Expression patterns of xenobiotic metabolizing enzymes in tumor and adjacent normal mucosa tissues among patients with colorectal cancer: The ColoCare Study

Background: Xenobiotic metabolizing enzymes (XMEs) play a critical role in the activation and detoxification of several carcinogens. However, the role of XMEs in colorectal carcinogenesis is unclear. Methods: We investigated the expression of XMEs in human colorectal tissues among n=71 stage I-IV colorectal cancer (CRC) patients from the ColoCare Study. Transcriptomic profiling using paired colorectal tumor and adjacent normal mucosa tissues of XMEs (GSTM1,GSTA1,UGT1A8,UGT1A10,CYP3A4,CYP2C9,GSTP1,CYP2W1) by RNA microarray was compared using Wilcoxon rank-sum tests. We assessed associations between clinicopathologic, dietary, and lifestyle-related factors and XME expression with linear regression models. Results: GSTM1, GSTA1, UGT1A8, UGT1A10, CYP3A4 were all statistically significantly downregulated in colorectal tumor relative to normal mucosa tissues (all p≤0.03). Women had significantly higher expression of GSTM1 in normal tissues compared to men (β=0.37,p-value=0.02). By tumor site, CYP2C9 expression was lower in normal mucosa among rectal cancer patients versus colon cancer cases (β=-0.21,p-value=0.0005). Smokers demonstrated higher CYP2C9 expression levels in normal mucosa (β=0.17,p=0.02) when compared with non-smokers. Individuals who used NSAIDs had higher GSTP1 tumor expression compared to non-NSAID users (β=0.17,p=0.03). Higher consumption of cooked vegetables (>1x/week) was associated with higher CYP3A4 expression in colorectal tumor tissues (β=0.14,p=0.007). Conclusions: XMEs have lower expression in colorectal tumor relative to normal mucosa tissues and may modify colorectal carcinogenesis via associations with clinical, lifestyle- and dietary-related factors. Impact: Better understanding into the role of drug-metabolizing enzymes in CRC may reveal biological differences that contribute to cancer development as well as treatment response, leading to clinical implications in CRC prevention and management.