Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis

Nobuyuki Kakiuchi, Kenichi Yoshida, Motoi Uchino, Takako Kihara, Kotaro Akaki, Yoshikage Inoue, Kenji Kawada, Satoshi Nagayama, Akira Yokoyama, Shuji Yamamoto, Minoru Matsuura, Takahiro Horimatsu, Tomonori Hirano, Norihiro Goto, Yasuhide Takeuchi, Yotaro Ochi, Yusuke Shiozawa, Yasunori Kogure, Yosaku Watatani, Yoichi Fujii, Soo Ki Kim, Ayana Kon, Keisuke Kataoka, Tetsuichi Yoshizato, Masahiro M. Nakagawa, Akinori Yoda, Yasuhito Nanya, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Eiji Sugihara, Taka-aki Sato, Takashi Maruyama, Hiroyuki Miyoshi, Makoto Mark Taketo, Jun Oishi, Ryosaku Inagaki, Yutaka Ueda, Shinya Okamoto, Hideaki Okajima, Yoshiharu Sakai, Takaki Sakurai, Hironori Haga, Seiichi Hirota, Hiroki Ikeuchi, Hiroshi Nakase, Hiroyuki Marusawa, Tsutomu Chiba, Osamu Takeuchi, Satoru Miyano, Hiroshi Seno and Seishi Ogawa ()
Additional contact information
Nobuyuki Kakiuchi: Kyoto University
Kenichi Yoshida: Kyoto University
Motoi Uchino: Hyogo College of Medicine
Takako Kihara: Hyogo College of Medicine
Kotaro Akaki: Kyoto University
Yoshikage Inoue: Kyoto University
Kenji Kawada: Kyoto University
Satoshi Nagayama: Cancer Institute Hospital, Japanese Foundation for Cancer Research
Akira Yokoyama: Kyoto University
Shuji Yamamoto: Kyoto University
Minoru Matsuura: Kyoto University
Takahiro Horimatsu: Kyoto University
Tomonori Hirano: Kyoto University
Norihiro Goto: Kyoto University
Yasuhide Takeuchi: Kyoto University
Yotaro Ochi: Kyoto University
Yusuke Shiozawa: Kyoto University
Yasunori Kogure: Kyoto University
Yosaku Watatani: Kyoto University
Yoichi Fujii: Kyoto University
Soo Ki Kim: Kyoto University
Ayana Kon: Kyoto University
Keisuke Kataoka: Kyoto University
Tetsuichi Yoshizato: Kyoto University
Masahiro M. Nakagawa: Kyoto University
Akinori Yoda: Kyoto University
Yasuhito Nanya: Kyoto University
Hideki Makishima: Kyoto University
Yuichi Shiraishi: The University of Tokyo
Kenichi Chiba: The University of Tokyo
Hiroko Tanaka: The University of Tokyo
Masashi Sanada: Kyoto University
Eiji Sugihara: University of Tsukuba
Taka-aki Sato: University of Tsukuba
Takashi Maruyama: Akita University Graduate School of Medicine
Hiroyuki Miyoshi: Kyoto University
Makoto Mark Taketo: Kyoto University
Jun Oishi: Sumitomo Dainippon Pharma
Ryosaku Inagaki: Kyoto University
Yutaka Ueda: Sumitomo Dainippon Pharma
Shinya Okamoto: Kyoto University
Hideaki Okajima: Kyoto University
Yoshiharu Sakai: Kyoto University
Takaki Sakurai: Kyoto University Hospital
Hironori Haga: Kyoto University
Seiichi Hirota: Hyogo College of Medicine
Hiroki Ikeuchi: Hyogo College of Medicine
Hiroshi Nakase: Kyoto University
Hiroyuki Marusawa: Kyoto University
Tsutomu Chiba: Kyoto University
Osamu Takeuchi: Kyoto University
Satoru Miyano: The University of Tokyo
Hiroshi Seno: Kyoto University
Seishi Ogawa: Kyoto University

Nature, 2020, vol. 577, issue 7789, 260-265

Abstract: Abstract Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1–3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

Date: 2020
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DOI: 10.1038/s41586-019-1856-1

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