RT Journal Article SR Electronic T1 The mutational profile and clonal landscape of the inflammatory bowel disease affected colon JF bioRxiv FD Cold Spring Harbor Laboratory SP 832014 DO 10.1101/832014 A1 Sigurgeir Olafsson A1 Rebecca E. McIntyre A1 Tim Coorens A1 Tim Butler A1 Philip Robinson A1 Henry Lee-Six A1 Mathijs A. Sanders A1 Kenneth Arestang A1 Claire Dawson A1 Monika Tripathi A1 Konstantina Strongili A1 Yvette Hooks A1 Michael R. Stratton A1 Miles Parkes A1 Inigo Martincorena A1 Tim Raine A1 Peter J. Campbell A1 Carl A. Anderson YR 2019 UL http://biorxiv.org/content/early/2019/11/11/832014.abstract AB Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers1–3 but our understanding of the effects of IBD on the mutational profile and clonal structure of the colon is limited. Here, we isolated and whole-genome sequenced 370 colonic crypts from 45 IBD patients, and compared these to 413 crypts from 41 non-IBD controls. We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon, and we did not detect an IBD-specific mutational process. 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 also found that non-synonymous mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients. With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia and point to potential therapeutic targets for IBD.