N-nitroso compound exposure-associated transcriptomic profiles are indicative of an increased risk for colorectal cancer

Abstract

Endogenous formation of N-nitroso compounds (NOCs), which are known animal carcinogens, could contribute to human carcinogenesis but definitive evidence is still lacking. To investigate the relevance of NOCs in human colorectal cancer (CRC) development, we analyzed whole genome gene expression modifications in human colon biopsies in relation to fecal NOC exposure. We had a particular interest in patients suffering from intestinal inflammation as this may stimulate endogenous NOC formation, and consequently predispose to CRC risk. Inflammatory bowel disease (IBD) patients diagnosed with ulcerative colitis and irritable bowel syndrome patients without inflammation, serving as controls, were therefore recruited. Fecal NOC were demonstrated in the majority of subjects. By associating gene expression levels of all subjects to fecal NOC levels, we identified a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may potentially induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending NOC-induced carcinogenesis. In addition, pro-inflammatory transcriptomic modifications were identified in visually non-inflamed regions of the IBD colon. However, fecal NOC levels were slightly but not significantly increased in IBD patients, suggesting that inflammation did not strongly stimulate NOC formation. We conclude that NOC exposure is associated with gene expression modifications in the human colon that may suggest a potential role of these compounds in CRC development.

0908 The role of red and processed meat in colorectal cancer development: A perspective

“…Recently, human studies have demonstrated that indeed under normal dietary conditions urinary markers of exposure to N-nitroso compounds are associated with micronucleus frequencies, a validated marker of carcinogenic risk, as well as with gene expression changes that are involved in cancer development (Hebels, Jennen, et al, 2011). Similar gene expression changes were also found in colonic biopsy material after a human intervention study with red meat (Hebels, Sveje, et al, 2011;Hebels et al, 2012).…”

Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association

“…Members of the latter NOC category, however, were found to activate a rich set of transcripts of the cell cycle and apoptosis pathways in Caco-2 cells and in biopsies of human volunteers (Hebels et al, 2009;Hebels et al, 2011). An ensuing report of the same research group showed ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT 24 that a diet rich in red meat, in patients suffering either from inflammatory or irritable bowel syndrome, correlates positively to activation of a range of pro-neoplastic genes, as revealed by gene expression analysis.…”

Dietary exposure to meat-related carcinogenic substances: is there a way to estimate the risk?

“…colorectal cancer. Colorectal cancer is the third most common type of cancer in humans (Hebels et al, 2011;Kim et al, 2013). Nevertheless, in meat several potential anticarcinogens can be found including omega-3 polyunsaturated fatty acids (especially in fish) or conjugated linoleic acid (present in ruminant meats, e.g.…”