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Title: Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis
Authors: Kakiuchi, Nobuyuki  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-4893-5414 (unconfirmed)
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  kyouindb  KAKEN_id
Ochi, Yotaro  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0001-8472-6164 (unconfirmed)
Shiozawa, Yusuke
Kogure, Yasunori
Watatani, Yosaku
Fujii, Yoichi
Kim, Soo Ki
Kon, Ayana  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0001-7237-0180 (unconfirmed)
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  kyouindb  KAKEN_id
Hirota, Seiichi
Ikeuchi, Hiroki
Nakase, Hiroshi
Marusawa, Hiroyuki
Chiba, Tsutomu
Takeuchi, Osamu  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-1260-6232 (unconfirmed)
Miyano, Satoru
Seno, Hiroshi
Ogawa, Seishi
Author's alias: 垣内, 伸之
吉田, 健一
内野, 基
木原, 貴子
赤木, 宏太朗
河田, 健二
長山, 聡
横山, 顕礼
山本, 修司
松浦, 稔
堀松, 高博
竹内, 康英
越智, 陽太郎
塩澤, 裕介
木暮, 泰寛
綿谷, 陽作
金, 秀基
昆, 彩奈
片岡, 圭亮
吉里, 哲一
中川, 正宏
依田, 成玄
南谷, 泰仁
牧島, 秀樹
白石, 友一
千葉, 健一
真田, 昌
杉原, 英志
佐藤, 孝明
丸山, 貴司
三好, 弘之
武藤, 誠
稲垣, 良作
岡島, 英明
坂井, 義治
桜井, 孝規
羽賀, 博典
廣田, 誠一
池内, 浩基
仲瀬, 裕志
丸澤, 宏之
千葉, 勉
竹内, 理
宮野, 悟
妹尾, 浩
小川, 誠司
Keywords: Colon cancer
Evolutionary biology
Ulcerative colitis
Issue Date: 9-Jan-2020
Publisher: Springer Nature
Journal title: Nature
Volume: 577
Start page: 260
End page: 265
Abstract: Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1, 2, 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.
Description: 潰瘍性大腸炎による上皮再構築メカニズムと発がんとの関係を解明 --IL-17シグナル経路に変異を獲得した上皮細胞は発がん過程で陰性に選択される--. 京都大学プレスリリース. 2019-12-20.
Rights: This is the accepted manuscript of the article, which has been published in final form at https://doi.org/10.1038/s41586-019-1856-1.
The full-text file will be made open to the public on 18 June 2020 in accordance with publisher's 'Terms and Conditions for Self-Archiving'.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
URI: http://hdl.handle.net/2433/245358
DOI(Published Version): 10.1038/s41586-019-1856-1
PubMed ID: 31853061
Related Link: https://www.kyoto-u.ac.jp/ja/research-news/2019-12-20
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