P042 Distinct gene expression profile associated to inflammation and neoplastic progression in longstanding ulcerative colitis

Abstract

Background One of the main drivers of colitis associated colorectal cancer (CA-CRC) is suspected to be long-standing mucosal inflammation, but far from all colitis patients develop cancer. We analyzed mucosal gene expression profiles in ulcerative colitis (UC) patients who have progressed to neoplasia (progressors) compared to those who have not (non-progressors) in order to identify underlying mechanisms for neoplastic progression in UC patients. Methods We performed transcriptome profiling on 143 mucosal samples from non-neoplastic colon segments of 14 UC progressors and 30 UC non-progressors from the prospective CA-CRC cohorts from Lovisenberg Diakonale- and Akershus University Hospitals in Norway. Differentially expressed genes were determined using SurePrint G3 human gene expression 60K microarray (Agilent Tech Inc.). Results 609 genes were differentially expressed between non-progressor- and progressor inflamed tissue, 24 genes between non-progressor- and progressor non-inflamed tissue, 404 genes between non-progressor non-inflamed- and -inflamed tissue and 26 genes between progressor non-inflamed- and inflamed tissue. In inflamed mucosa, genes related to metabolic processes such as xenobiotic- as well as carbohydrate and lipid metabolism were significantly higher expressed in progressors compared to non-progressors. Genes related to innate and adaptive immune responses were expressed at significantly lower levels. These main traits were not influenced by type of inflammation but apparent in both, chronic- and chronic active inflammation. However, chronic inflamed mucosa of progressors were also characterised by dysregulation of processes related to chromatin organization. Treatment with immunomodulators and biologics were equally distributed in the groups. Restriction of the analysis to patients without treatment of these drugs did not significantly influence the main results. In non-inflamed mucosa, the gene expression profile of progressors and non-progressors were remarkably similar. In fact, within the positively and negatively enriched gene ontologies, only the gene S100P was significantly deregulated with a higher expression in non-inflamed mucosa of the progressors. Conclusion Upregulated detoxification as well as dysregulated immune response and chromatin organization may be underlying processes for neoplastic progression in ulcerative colitis. Our findings warrant further evaluation.