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Molecular characterization of limited ulcerative colitis reveals novel biology and predictors of disease extension.

BACKGROUND
Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension, is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension.


METHODS
We performed RNA sequence analysis of biopsies from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsies were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments.


RESULTS
Differentially expressed genes were identified in the endoscopically inflamed biopsies taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsies transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation and homeodomain pathways. A subset of these genes in inflamed biopsies was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and PARP14 was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsies of limited UC patients that subsequently extended.


CONCLUSION
Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.