Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis

• Published in: Nature (London) 2020-01, Vol.577 (7789), p.260-265
• Main Authors: Kakiuchi, Nobuyuki, Yoshida, Kenichi, Uchino, Motoi, Kihara, Takako, Akaki, Kotaro, Inoue, Yoshikage, Kawada, Kenji, Nagayama, Satoshi, Yokoyama, Akira, Yamamoto, Shuji, Matsuura, Minoru, Horimatsu, Takahiro, Hirano, Tomonori, Goto, Norihiro, Takeuchi, Yasuhide, Ochi, Yotaro, Shiozawa, Yusuke, Kogure, Yasunori, Watatani, Yosaku, Fujii, Yoichi, Kim, Soo Ki, Kon, Ayana, Kataoka, Keisuke, Yoshizato, Tetsuichi, Nakagawa, Masahiro M., Yoda, Akinori, Nanya, Yasuhito, Makishima, Hideki, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Sanada, Masashi, Sugihara, Eiji, Sato, Taka-aki, Maruyama, Takashi, Miyoshi, Hiroyuki, Taketo, Makoto Mark, Oishi, Jun, Inagaki, Ryosaku, Ueda, Yutaka, Okamoto, Shinya, Okajima, Hideaki, Sakai, Yoshiharu, Sakurai, Takaki, Haga, Hironori, Hirota, Seiichi, Ikeuchi, Hiroki, Nakase, Hiroshi, Marusawa, Hiroyuki, Chiba, Tsutomu, Takeuchi, Osamu, Miyano, Satoru, Seno, Hiroshi, Ogawa, Seishi
• Format: Article
• Language: English
• Subjects: 45/23; 631/208/182; 631/67/1504/1885/1393; 692/699/1503/257/1389; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Age; Analysis; Animals; Cancer; Carcinogenesis; Carcinogens; Cell Line, Tumor; Clonal selection; Cloning; Colitis, Ulcerative - genetics; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Disruption; Epithelium; Forecasts and trends; Gene mutations; Genetic aspects; Health risks; Humanities and Social Sciences; Humans; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin 17; Intestine; Medicin och hälsovetenskap; Mice; multidisciplinary; Mutants; Mutation; Mutation Rate; Negative selection; Phylogenetics; Physiology; Positive selection; Science; Science (multidisciplinary); Signal Transduction; Tissues; Transcription factors; Tumors; Ulcerative colitis
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-1856-1

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer 1 – 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. In patients with ulcerative colitis, chronic inflammation can lead to remodelling of the colorectal epithelium through positive selection of clones with mutations in genes related to IL-17 signalling, which, however, might be negatively selected during colitis-associated carcinogenesis.