Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis
Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis
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DOI：
10.1038/s41586-019-1856-1
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发表时间：
2020-01-09
期刊：
影响因子：
64.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Kakiuchi, Nobuyuki;Yoshida, Kenichi;Ogawa, Seishi
慢性炎症伴随着组织破坏和修复的循环，并与癌症风险增加有关（1-3）。然而，这些周期如何影响组织的克隆组成，特别是在癌症发展方面，仍然未知。本研究表明，在溃疡性结肠炎患者中，发炎的肠道经历了普遍克隆的广泛重塑，其中许多克隆通过获得通常涉及NFKBIZ、TRAF3IP2、ZC3H12A、PIGR和HNRNPF基因的突变而被积极选择，这些突变与IL-17和其他促炎信号的下调有关。溃疡性结肠炎中结肠炎相关癌症和非发育不良组织的突变谱差异很大，这表明在这两种组织中存在不同的正向选择机制。特别是，NFKBIZ突变在溃疡性结肠炎患者的上皮中非常普遍，但在散发性和结肠炎相关的癌症中很少发现，这表明NFKBIZ突变细胞在结直肠癌发生过程中被选中。为了进一步支持这种负选择，我们发现NFKBIZ突变小鼠的肿瘤形成明显减弱，并且在人类结直肠癌细胞中NFKBIZ的破坏损害了细胞竞争。我们的研究结果突出了炎症组织中常见和离散的克隆选择机制，揭示了意想不到的癌症脆弱性，可能潜在地用于结直肠癌的治疗。
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.