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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Vydáno v:	Cell Ročník 182; číslo 3; s. 672
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 06.08.2020
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2020.06.036