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Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis.

ABSTRACT: BACKGROUND:Accurate and reproducible measurement of expression of pro-inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements. AIM:To validate methods for measuring changes in gene expression in colonic biopsy samples. METHODS:Twelve colonic biopsies were obtained from each of six healthy controls, six patients with inactive UC and seven patients with active UC. Mayo endoscopic scores were used as a clinical reference standard. Quantitative PCR was used to assess mRNA expression of eight known inflammatory genes. The power to detect a reduction in gene expression in active vs. inactive UC was calculated using a linear mixed effect model. RESULTS:mRNA analysis of colonic biopsies is a sensitive and feasible approach for measuring inflammatory gene expression in colonic biopsies. Inflammatory biomarkers correlate with Mayo endoscopic subscores for each colonic region. For most genes, three rectal biopsies from two to four patients are required to detect changes in gene expression corresponding to active vs. inactive UC to achieve a power of 80% with an alpha of 0.05. CONCLUSION:Our data suggest that systematic measurement of inflammatory biomarkers at the mRNA level can be a valuable tool for hypothesis testing, and assessment of clinical activity and response to therapy in ulcerative colitis.

SUBMITTER: Boland BS

PROVIDER: S-EPMC4143528 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis.

Boland B S BS Boyle D L DL Sandborn W J WJ Firestein G S GS Levesque B G BG Hillman J J Zhang B B Proudfoot J J Eckmann L L Ernst P B PB Rivera-Nieves J J Pola S S Copur-Dahi N N Chang J T JT

Alimentary pharmacology & therapeutics 20140713 5

<h4>Background</h4>Accurate and reproducible measurement of expression of pro-inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements.<h4>Aim</h4>To validate methods for measuring changes in gene expression in colonic biopsy samples.<h4>Methods</h4>Twelve colonic biopsies were ...[more]

PMID: 25041724

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Project description:Objective: Ulcerative colitis (UC) is a chronic disease with rising incidence and unclear etiology. The application of mass spectrometry-based post-genomic analysis methods shall support the development of molecular biomarker signatures providing status information with regard to UC pathomechanisms. Design: Pathomechanisms characteristic for UC were assessed by proteome profiling of human tissue specimen, obtained from five distinct colon locations each of 12 patients. Systemic disease-associated alterations were investigated by mass spectrometry-based multi-omics analyses comprising proteins, metabolites and eicosanoids of plasma obtained from UC patients during disease and upon remission in comparison to healthy controls. Results: Proteome profiling results identified colitis-associated activation of neutrophils, macrophages, B- and T-cells, platelets, fibroblasts and endothelial cells and indicated hypoxic stress, as well as a general reduction of mitochondrial proteins accompanying the establishment of apparent healing-promoting activities as well as scar formation. While the immune cells mainly contributed pro-inflammatory proteins, the colitis-associated epithelial cells, fibroblasts, endothelial cells and platelets predominantly formed anti-inflammatory and healing-promoting proteins. Blood plasma proteomics indicated chronic inflammation and platelet activation, whereas plasma metabolomics identified disease-associated deregulation of bile acids, eicosanoids and gut microbiome-derived metabolites. Upon remission, several, but not all, molecular candidate biomarker levels recovered to normal levels. These findings may indicate that pathomechanisms related to gut functions, gut microbiome status, microvascular damage and metabolic dysregulation associated with hypoxia may do not resolve uniformly upon remission. Conclusions: The establishment of disease-associated biomarker profiles related to molecular UC pathomechanisms may support the establishment of bioassays with improved prognostic power aiding individualized therapy.

Dataset Information

Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis.

Publications

Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis.

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