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Somatic inflammatory gene mutations in human ulcerative colitis epithelium

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations 1 – 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 u...

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Bibliographic Details
Published in:Nature (London) 2020-01, Vol.577 (7789), p.254-259
Main Authors: 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
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Language:English
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Summary:With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations 1 – 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 mice 8 – 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. Whole-exome sequencing of colon organoids derived from patients with ulcerative colitis identifies somatic mutations in components of the IL-17 signalling pathway, which may confer a growth advantage to cells under inflammatory conditions.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-019-1844-5