Somatic Evolution in Non-neoplastic IBD-Affected Colon

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation lan...

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Bibliographic Details
Published in:Cell Vol. 182; no. 3; p. 672
Main Authors: Olafsson, Sigurgeir, McIntyre, Rebecca E, Coorens, Tim, Butler, Timothy, Jung, Hyunchul, Robinson, Philip S, Lee-Six, Henry, Sanders, Mathijs A, Arestang, Kenneth, Dawson, Claire, Tripathi, Monika, Strongili, Konstantina, Hooks, Yvette, Stratton, Michael R, Parkes, Miles, Martincorena, Inigo, Raine, Tim, Campbell, Peter J, Anderson, Carl A
Format: Journal Article
Language:English
Published: United States 06.08.2020
Subjects:
Adult
Aged
Aged, 80 and over
Aging - genetics
Clonal Evolution - genetics
Clonal Evolution - immunology
Colitis - genetics
Colitis - metabolism
Colitis, Ulcerative - genetics
Colitis, Ulcerative - metabolism
Crohn Disease - genetics
Crohn Disease - metabolism
DNA-Binding Proteins - genetics
Epithelial Cells - metabolism
Epithelial Cells - pathology
F-Box-WD Repeat-Containing Protein 7 - genetics
Female
Humans
INDEL Mutation
Inflammatory Bowel Diseases - genetics
Inflammatory Bowel Diseases - immunology
Inflammatory Bowel Diseases - metabolism
Inflammatory Bowel Diseases - pathology
Interleukin-17 - metabolism
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Male
Middle Aged
Mutation Rate
Phylogeny
Point Mutation
Receptors, Cell Surface - genetics
Ribonucleases - genetics
Toll-Like Receptors - genetics
Transcription Factors - genetics
Whole Genome Sequencing
somatic mutations
PIGR
mutational signatures
ZC3H12A
Crohn's disease
mutation rate
ulcerative colitis
IL17
intestinal epithelia
inflammatory bowel disease
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary:Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. 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, 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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2020.06.036