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Nanki, Kosaku; Fujii, Masayuki; Shimokawa, Mariko; Matano, Mami; Nishikori, Shingo; Date, Shoichi; Takano, Ai; Toshimitsu, Kohta; Ohta, Yuki; Takahashi, Sirirat; Sugimoto, Shinya; Ishimaru, Kazuhiro; Kawasaki, Kenta; Nagai, Yoko; Ishii, Ryota; Yoshida, Kosuke; Sasaki, Nobuo; Hibi, Toshifumi; Ishihara, Soichiro; Kanai, Takanori; Sato, Toshiro
Nature (London), 01/2020, Volume: 577, Issue: 7789Journal Article
With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations . 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 mice , 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.
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