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Colonic mucosal gene expression profile associated with neoplastic progression in longstanding ulcerative colitis

ABSTRACT: Introduction: Many gene expression studies of colitis-associated colorectal cancer (CA-CRC) in patients with ulcerative colitis (UC) have focused on identification of molecular drivers of progression of UC to CA- CRC. However, they have primarily studied cancerous mucosal biopsies, an approach which primarily may identify the characteristics of the established cancer mucosa and not the early molecular events driving the progression. Long-standing mucosal inflammation is suspected to be one of the main drivers of CA-CRC. Still, not all patients with UC progress and develop cancer. We hypothesise that patients with UC, who have progressed to neoplasia (progressors), have a different molecular profile of inflammation than non-progressors. Methods: We performed transcriptome profiling on 143 mucosal biopsies from non-neoplastic colonic segments of 14 UC progressors and 30 UC non-progressors. In addition, we performed profiling of lymphocyte infiltration to the mucosa of biopsies taken adjacent to biopsies used for transcriptomic analysis. Results: We found a characteristic gene expression profile for inflamed mucosa of UC progressors, which primarily is associated with progression of UC to dysplasia or cancer as opposed to long duration of disease. The gene expression profile suggests that the inflamed tissue of UC progressors is negatively enriched for biological processes such as adaptive immune responses and complement system activity and positively enriched for biological processes related to detoxification. Moreover, we found that the microenvironment in the inflamed mucosa of progressors differs from non-progressors by having fewer infiltrating B cells and less lymphoid aggregates. Conclusions: We found that inflammation of UC patients, who have progressed to dysplasia or cancer, has a different gene expression profile than that of UC non-progressors. Importantly, this profile was primarily associated with progression of disease as opposed to duration of disease. The inflamed mucosa of UC progressors may have lower levels of lymphoid organ-initiating and immune cell- attracting signals and fewer immune cells infiltrating the mucosa. Consequently, progressors may lack the ability to mount sufficient adaptive immune responses necessary to counteract driving forces of malignant transformation in UC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236055 | GEO | 2025/10/20

REPOSITORIES: GEO

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Project description:Background & Aims: Genome-wide gene expression (GWGE) profiles of mucosal colonic biopsies have suggested the existence of a continuous inflammatory state in quiescent ulcerative colitis (UC). The aim of this study was to use DNA microarray-based GWGE profiling of mucosal colonic biopsies and isolated colonocytes from UC patients and controls in order to identify the cell types responsible for the continuous inflammatory state. Methods: Adjacent mucosal colonic biopsies were obtained endoscopically from the descending colon in patients with active UC (n=8), quiescent UC (n=9), and with irritable bowel syndrome (controls, n=10). After isolation of colonocytes and subsequent extraction of total RNA, GWGE data were acquired using Human Genome U133 Plus 2.0 GeneChip Array (Affymetrix, Santa Clara, CA). Data analysis was carried out by principal component analysis and projection to latent structure-discriminant analysis using the SIMCA-P11 software (Umetrics, Umeå, Sweden). Results: A clear separation between active UC, quiescent UC and control biopsies were found, whereas the model for the colonocytes was unable to distinguish between quiescent UC and controls. The differentiation between quiescent UC and control biopsies was governed by unique profiles containing gene expressions with significant fold changes. These primarily belonged to the family of homeostatic chemokines revealing a plausible explanation to the abnormal regulated innate immune response seen in patients with UC. Conclusion: This study has demonstrated the presence of a continuous inflammatory state in quiescent UC, which seems to reflect an altered gene expression profile of lamina propria cells. Keywords: Colonocytes, continuous inflammation, mucosal colonic biopsies, gene expression profiles Adjacent mucosal colonic biopsies were attained endoscopically from the descending colon in patients with active UC (n=8), quiescent UC (n=9), and in controls (n=10). After extraction of total RNA, genome-wide gene expression data were acquired using Human Genome U133 Plus 2.0 GeneChip Array (Affymetrix, Santa Clara, CA). Amplification was required to obtain sufficient amounts of labelled complementary RNA (cRNA) target for analysis with arrays. Data analysis was carried out by principal component analysis and projection to latent structure-discriminant analysis using the SIMCA-P11 software (Umetrics, Umeå, Sweden).

Project description:Background and aims: Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls (HC), taken from macroscopically non-inflamed tissue from the terminal ileum and three colonic locations with the objective of identifying abnormal molecules that might be involved in disease development. Methods: Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 UC, 26 HC and 14 patients with CrohnM-bM-^@M-^Ys disease. Differential gene expression analysis was performed at each tissue location separately and results were then meta-analysed using FisherM-bM-^@M-^Ys method. Significantly differentially expressed genes were validated using qPCR. Gene location within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing. Results: Seven probes were abnormally expressed throughout the colon in UC patients with Family with sequence similarity member 5 C (FAM5C) being the most significantly underexpressed. Attenuated expression of FAM5C in UC was independent of inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy approximately 23 months later. FAM5C is localised to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter. Conclusion: Genome-wide expression analysis of non-inflamed mucosal biopsies from UC patients identified FAM5C as significantly under-expressed throughout the colon in a major sub-set of patients with UC. Low levels of this gene could predispose to or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition. Total RNA was extracted from the intestinal biopsies taken from macroscopically normal mucosa in the rectum, descending colon, ascending colon and terminal ileum in clinically quiescent Ulcerative colitis and Crohn's disease patients and compared to healthy controls. Normalized data for 26,261 probes out of 47,323 only. Criteria for inclusion not specified. The non-normalized matrix contains the complete non-normalized data for all probes.

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Colonic mucosal gene expression profile associated with neoplastic progression in longstanding ulcerative colitis

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