Nature:溃疡性结肠炎的体细胞突变特征
创作:szx 审核:szx 2019年12月24日
  • 构建76个人结肠类器官,分别来自健康人、溃疡性结肠炎(UC)患者的非炎症部位、UC患者的炎症部位、UC+结直肠癌患者的炎症+癌变部位;
  • UC患者的炎症部位中,IL-17信号通路相关基因(NFKBIZ、ZC3H12A、PIGR等)突变显著累积,这些突变在结直肠癌中很少出现;
  • 部分基因(NFKBIZ等)的敲除可抵抗IL-17A引起的促细胞凋亡性应答,提示炎症环境可促进适应性突变的产生;
  • 部分基因的特定突变与UC易感性相关,提示这些基因也可能促进UC的发病。
主编推荐语
szx
随着衰老的进程,人体组织中带有致癌突变的体细胞克隆将逐渐扩增。Nature上发表的一项最新研究,鉴定出了溃疡性结肠炎(UC)患者的结肠炎症部位中的特定体细胞突变模式,发现与IL-17信号通路相关的基因突变显著累积,而这些基因突变在同时患有结直肠癌的UC患者中很少发生。
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Nature [IF:42.778]

Somatic inflammatory gene mutations in human ulcerative colitis epithelium

溃疡性结肠炎患者上皮中的体细胞炎症基因突变

10.1038/s41586-019-1844-5

2019-12-18, Article

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With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1,2,3,4,5,6,7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling—including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8,9,10,11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

First Authors:
Kosaku Nanki,Masayuki Fujii

Correspondence Authors:
Toshiro Sato

All Authors:
Kosaku Nanki,Masayuki Fujii,Mariko Shimokawa,Mami Matano,Shingo Nishikori,Shoichi Date,Ai Takano,Kohta Toshimitsu,Yuki Ohta,Sirirat Takahashi,Shinya Sugimoto,Kazuhiro Ishimaru,Kenta Kawasaki,Yoko Nagai,Ryota Ishii,Kosuke Yoshida,Nobuo Sasaki,Toshifumi Hibi,Soichiro Ishihara,Takanori Kanai,Toshiro Sato

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