Elevated colonic mucin expression correlates with extended time to surgery for ulcerative colitis patients

Melanie A. Eshelman, N. Arjun Jeganathan, Kathleen M. Schieffer, Bryan P. Kline, Megan Mendenhall, Sue Deiling, Leonard Harris, Walter A. Koltun, Gregory S. Yochum

Research output: Contribution to journalArticle

Abstract

Background & Aims: Both genetic and environmental factors contribute to the development and persistence of ulcerative colitis (UC). As supported by differential responses to therapy, multiple subclasses of disease likely comprise UC. We reasoned that profiling the colonic transcriptomes may offer one approach to molecular subtype UC. Methods: We conducted RNA-sequencing (RNA-seq) on full-thickness colonic tissues from 26 UC patients undergoing colectomy. Hierarchal clustering from transcriptomic data identified disease subsets. Subsets were characterized using differential gene expression analysis, cell type deconvolution, and network analysis. Results: We identified two UC subsets that were distinguished by 957 differentially expressed genes. Cluster 1 was enriched in genes associated with intestinal epithelial cell (IEC) differentiation, while cluster 2 was enriched in genes associated with epithelial-to-mesenchymal transition (EMT) and inflammatory responses. Cluster 1 was associated with an extended time from diagnosis to colectomy [hazard ratio = 0.45 (95% CI: 0.14-0.88); p=0.03]. Of cluster 1 genes, elevated MUC5B, MUC4, and MUC2 expression displayed the strongest correlation with increased time to surgery [hazard ratio = 0.37 (95% CI: 0.11-0.61); p=0.0044]. Conclusions: Our transcriptome analysis indicates that UC can be sub-classified into at least two molecular signatures. We found that elevated mucin gene expression correlated with prolonged time to colectomy following diagnosis. This work identified MUC5B, MUC4, and MUC2 as potential prognostic indicators of disease severity, as reflected in time to surgery after diagnosis.

Original languageEnglish (US)
Pages (from-to)405-413
Number of pages9
JournalJournal of Gastrointestinal and Liver Diseases
Volume28
Issue number4
DOIs
StatePublished - Jan 1 2019

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Mucins
Ulcerative Colitis
Colectomy
Gene Expression Profiling
Genes
RNA Sequence Analysis
Gene Expression
Epithelial-Mesenchymal Transition
Multigene Family
Cluster Analysis
Cell Differentiation
Epithelial Cells
RNA

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Eshelman, M. A., Jeganathan, N. A., Schieffer, K. M., Kline, B. P., Mendenhall, M., Deiling, S., ... Yochum, G. S. (2019). Elevated colonic mucin expression correlates with extended time to surgery for ulcerative colitis patients. Journal of Gastrointestinal and Liver Diseases, 28(4), 405-413. https://doi.org/10.15403/jgld-250
Eshelman, Melanie A. ; Jeganathan, N. Arjun ; Schieffer, Kathleen M. ; Kline, Bryan P. ; Mendenhall, Megan ; Deiling, Sue ; Harris, Leonard ; Koltun, Walter A. ; Yochum, Gregory S. / Elevated colonic mucin expression correlates with extended time to surgery for ulcerative colitis patients. In: Journal of Gastrointestinal and Liver Diseases. 2019 ; Vol. 28, No. 4. pp. 405-413.
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abstract = "Background & Aims: Both genetic and environmental factors contribute to the development and persistence of ulcerative colitis (UC). As supported by differential responses to therapy, multiple subclasses of disease likely comprise UC. We reasoned that profiling the colonic transcriptomes may offer one approach to molecular subtype UC. Methods: We conducted RNA-sequencing (RNA-seq) on full-thickness colonic tissues from 26 UC patients undergoing colectomy. Hierarchal clustering from transcriptomic data identified disease subsets. Subsets were characterized using differential gene expression analysis, cell type deconvolution, and network analysis. Results: We identified two UC subsets that were distinguished by 957 differentially expressed genes. Cluster 1 was enriched in genes associated with intestinal epithelial cell (IEC) differentiation, while cluster 2 was enriched in genes associated with epithelial-to-mesenchymal transition (EMT) and inflammatory responses. Cluster 1 was associated with an extended time from diagnosis to colectomy [hazard ratio = 0.45 (95{\%} CI: 0.14-0.88); p=0.03]. Of cluster 1 genes, elevated MUC5B, MUC4, and MUC2 expression displayed the strongest correlation with increased time to surgery [hazard ratio = 0.37 (95{\%} CI: 0.11-0.61); p=0.0044]. Conclusions: Our transcriptome analysis indicates that UC can be sub-classified into at least two molecular signatures. We found that elevated mucin gene expression correlated with prolonged time to colectomy following diagnosis. This work identified MUC5B, MUC4, and MUC2 as potential prognostic indicators of disease severity, as reflected in time to surgery after diagnosis.",
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Eshelman, MA, Jeganathan, NA, Schieffer, KM, Kline, BP, Mendenhall, M, Deiling, S, Harris, L, Koltun, WA & Yochum, GS 2019, 'Elevated colonic mucin expression correlates with extended time to surgery for ulcerative colitis patients', Journal of Gastrointestinal and Liver Diseases, vol. 28, no. 4, pp. 405-413. https://doi.org/10.15403/jgld-250

Elevated colonic mucin expression correlates with extended time to surgery for ulcerative colitis patients. / Eshelman, Melanie A.; Jeganathan, N. Arjun; Schieffer, Kathleen M.; Kline, Bryan P.; Mendenhall, Megan; Deiling, Sue; Harris, Leonard; Koltun, Walter A.; Yochum, Gregory S.

In: Journal of Gastrointestinal and Liver Diseases, Vol. 28, No. 4, 01.01.2019, p. 405-413.

Research output: Contribution to journalArticle

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T1 - Elevated colonic mucin expression correlates with extended time to surgery for ulcerative colitis patients

AU - Eshelman, Melanie A.

AU - Jeganathan, N. Arjun

AU - Schieffer, Kathleen M.

AU - Kline, Bryan P.

AU - Mendenhall, Megan

AU - Deiling, Sue

AU - Harris, Leonard

AU - Koltun, Walter A.

AU - Yochum, Gregory S.

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N2 - Background & Aims: Both genetic and environmental factors contribute to the development and persistence of ulcerative colitis (UC). As supported by differential responses to therapy, multiple subclasses of disease likely comprise UC. We reasoned that profiling the colonic transcriptomes may offer one approach to molecular subtype UC. Methods: We conducted RNA-sequencing (RNA-seq) on full-thickness colonic tissues from 26 UC patients undergoing colectomy. Hierarchal clustering from transcriptomic data identified disease subsets. Subsets were characterized using differential gene expression analysis, cell type deconvolution, and network analysis. Results: We identified two UC subsets that were distinguished by 957 differentially expressed genes. Cluster 1 was enriched in genes associated with intestinal epithelial cell (IEC) differentiation, while cluster 2 was enriched in genes associated with epithelial-to-mesenchymal transition (EMT) and inflammatory responses. Cluster 1 was associated with an extended time from diagnosis to colectomy [hazard ratio = 0.45 (95% CI: 0.14-0.88); p=0.03]. Of cluster 1 genes, elevated MUC5B, MUC4, and MUC2 expression displayed the strongest correlation with increased time to surgery [hazard ratio = 0.37 (95% CI: 0.11-0.61); p=0.0044]. Conclusions: Our transcriptome analysis indicates that UC can be sub-classified into at least two molecular signatures. We found that elevated mucin gene expression correlated with prolonged time to colectomy following diagnosis. This work identified MUC5B, MUC4, and MUC2 as potential prognostic indicators of disease severity, as reflected in time to surgery after diagnosis.

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