Somatic inflammatory gene mutations in human ulcerative colitis epithelium

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 and Toshiro Sato ()
Additional contact information
Kosaku Nanki: Keio University School of Medicine
Masayuki Fujii: Keio University School of Medicine
Mariko Shimokawa: Keio University School of Medicine
Mami Matano: Keio University School of Medicine
Shingo Nishikori: Keio University School of Medicine
Shoichi Date: Keio University School of Medicine
Ai Takano: Keio University School of Medicine
Kohta Toshimitsu: Keio University School of Medicine
Yuki Ohta: Keio University School of Medicine
Sirirat Takahashi: Keio University School of Medicine
Shinya Sugimoto: Keio University School of Medicine
Kazuhiro Ishimaru: Keio University School of Medicine
Kenta Kawasaki: Keio University School of Medicine
Yoko Nagai: Otsuka Pharmaceutical Company
Ryota Ishii: Keio University Hospital
Kosuke Yoshida: Keio University School of Medicine
Nobuo Sasaki: Keio University School of Medicine
Toshifumi Hibi: Keio University School of Medicine
Soichiro Ishihara: The University of Tokyo
Takanori Kanai: Keio University School of Medicine
Toshiro Sato: Keio University School of Medicine

Nature, 2020, vol. 577, issue 7789, 254-259

Abstract: Abstract With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1–7. 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 mice8–11, 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.

Date: 2020
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DOI: 10.1038/s41586-019-1844-5

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