Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. Here, we whole-genome sequenced 447 colonic crypts from 46 IBD patients, and compared these to 412 crypts from 41 non-IBD controls. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.
Highlights
Inflammatory bowel disease (IBD) is a debilitating disease characterized by repeated flares of intestinal inflammation
IBD More Than Doubles the Mutation Rate of Normal Colonic Epithelium We used laser capture microdissection (LCM) to isolate 446 colonic crypts from endoscopic biopsies taken from 28 ulcerative colitis (UC) patients and 18 Crohn’s disease (CD) patients (Table S1)
To assess if IBD is associated with a difference in the mutation burden of the colonic epithelium, we combined our data with data from 412 crypts sequenced as part of our recent study of somatic mutations in normal colon (Lee-Six et al, 2019)
Summary
Inflammatory bowel disease (IBD) is a debilitating disease characterized by repeated flares of intestinal inflammation. The two major subtypes of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), are distinguished by the location, continuity, and nature of the inflammatory lesions. UC affects only the large intestine, spreading continuously from the distal to proximal colon, whereas CD most commonly affects the small and large intestine and is characterized by discontinuous patches of inflammation. Cancer risk is associated with the duration, extent, and severity of disease, and cancers tend to occur earlier in life in IBD patients (Lutgens et al, 2013; Beaugerie and Itzkowitz, 2015; Adami et al, 2016). Patients require regular endoscopic screening and may undergo prophylactic colectomy to mitigate this risk (Beaugerie and Itzkowitz, 2015; Adami et al, 2016)
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