Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; University of Cambridge, Department of Paediatrics, Cambridge CB2 0QQ, UK.
Cell. 2020 Aug 6;182(3):672-684.e11. doi: 10.1016/j.cell.2020.06.036. Epub 2020 Jul 21.
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.
炎症性肠病（IBD）是一种慢性炎症性疾病，与胃肠道癌症的风险增加有关。我们对 46 名 IBD 患者的 446 个结肠隐窝进行了全基因组测序，并将这些数据与我们之前关于正常结肠突变景观的研究中的 412 个非 IBD 对照隐窝进行了比较。受影响的结肠上皮细胞的平均突变率是非健康结肠的 2.4 倍，这种增加主要是由正常结肠中普遍存在的突变过程加速所驱动的。与正常结肠不同，正常结肠中隐窝外的克隆扩张很少见，我们观察到广泛的毫米级克隆扩张。我们在 IBD 中发现了 ARID1A、FBXW7、PIGR、ZC3H12A 和白细胞介素 17 和 Toll 样受体途径中的基因的非同义突变，这些突变受到正选择。这些结果表明在结肠炎相关结肠中有不同的选择机制，并且体细胞突变可能在 IBD 发病机制中起因果作用。
