Colonic Mucosal Gene Expression Profile in Patients with Neoplastic Progression in Longstanding Ulcerative Colitis

Lene Alsøe,1,2,* Stephan Andreas Brackmann,2,3,* Yohan Lefol,2,4 Anna Berit Wennerström,5 Yan Liu,5 Rosa Ana Risques,6 Solveig Norheim Andersen,2 Hilde Loge Nilsen1,2,4 1Department of Microbiology, Oslo University Hospital, Oslo, Norway; 2Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 3Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway; 4CRESCO - Centre for Embryology and Healthy Development, University of Oslo, Oslo, Norway; 5Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway; 6Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA*These authors contributed equally to this workCorrespondence: Hilde Loge Nilsen, Email [email protected] Stephan Andreas Brackmann, Email [email protected]: Long-standing mucosal inflammation is suspected to be one of the main drivers of colitis-associated colorectal cancer (CA-CRC), but far from all colitis patients develop cancer. Non-neoplastic mucosa located distant from neoplastic lesions may harbour early molecular events of carcinogenesis. We hypothesise that patients with UC who have progressed to neoplasia (progressors) exhibit a distinct molecular profile of mucosal inflammation from non-progressors.Patients and Methods: We performed transcriptomic profiling of 143 mucosal biopsies from non-neoplastic colonic segments of 14 UC progressors and 30 UC non-progressors using the Agilent SurePrint G3 human gene expression 60K microarray. Subsequently, we carried out gene set ontology analyses. In addition, we assessed lymphocyte infiltration to the mucosa of biopsies taken adjacent to biopsies used for transcriptomic analysis by immunohistochemistry.Results: Adjusting for molecular alterations associated with long disease duration, our findings revealed that UC Progressors’ inflamed mucosa has a distinct gene expression profile of 529 significantly deregulated genes, eg LTB, CXCL13, CD19, C3 and CYP4F3. The profile was negatively enriched for biological processes (BPs) such as adaptive immune responses and complement system activity and positively enriched for processes related to detoxification. The negatively enriched BPs were supported by the presence of fewer infiltrating B cells and less lymphoid aggregates in the microenvironment of the inflamed mucosa of progressors.Conclusion: The inflamed colonic mucosa from UC patients who have progressed to dysplasia or cancer has a different gene expression profile than that of UC non-progressors, suggesting lower levels of lymphoid organ-initiating and immune cell-attracting signals and fewer infiltrating immune cells to the mucosa. Consequently, progressors may lack the ability to mount sufficient adaptive immune responses necessary to counteract driving forces of malignant transformation in UC.Keywords: inflammatory bowel diseases, ulcerative colitis, colitis-associated neoplasms, gene expression profiling