Somatic evolution in non-neoplastic IBD-affected colon
| Autor: | Yvette Hooks, Monika Tripathi, Carl A. Anderson, Sigurgeir Olafsson, Tim Raine, Michael R. Stratton, Tim H. H. Coorens, Claire Dawson, Philip S. Robinson, Miles Parkes, Kenneth Arestang, Peter J. Campbell, Mathijs A. Sanders, Rebecca E. McIntyre, Konstantina Strongili, Inigo Martincorena, Hyunchul Jung, Henry Lee-Six, Tim Butler |
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| Přispěvatelé: | Hematology, Parkes, Miles [0000-0002-6467-0631], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Male
Aging Mutation rate mutation rate F-Box-WD Repeat-Containing Protein 7 ARID1A Somatic cell medicine.disease_cause Somatic evolution in cancer Inflammatory bowel disease Pathogenesis 0302 clinical medicine Crohn Disease INDEL Mutation PIGR Intestinal Mucosa Phylogeny Aged 80 and over Crohn's disease Mutation 0303 health sciences Interleukin-17 Toll-Like Receptors Middle Aged Colitis Ulcerative colitis 3. Good health DNA-Binding Proteins Female 030211 gastroenterology & hepatology Interleukin 17 ZC3H12A Adult Crypt mutational signatures Receptors Cell Surface Biology digestive system Article intestinal epithelia General Biochemistry Genetics and Molecular Biology Clonal Evolution 03 medical and health sciences Germline mutation Ribonucleases inflammatory bowel disease medicine Humans Point Mutation ulcerative colitis Aged 030304 developmental biology Whole Genome Sequencing IL17 Cancer Epithelial Cells Inflammatory Bowel Diseases medicine.disease digestive system diseases Cancer research somatic mutations Colitis Ulcerative 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Cell Cell, 182(3), 672-684.e11. Cell Press |
| ISSN: | 0092-8674 |
| Popis: | 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. Graphical Abstract Highlights • IBD-affected colons accrue substitutions and indels 2.4 and 7 times faster than normal • 17 signatures of mutational processes, including treatment • Millimeter-scale clonal expansions late in molecular time • Distinct mechanisms of positive selection of mutations in immune-related genes Whole-genome sequencing of inflammatory bowel disease patient samples allows insight into mutational burdens and processes associated with disease, including putative driver mutations positively selected in the diseased colon. |
| Databáze: | OpenAIRE |
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