The enhancer rare germline variation rs548071605 contributes to lung cancer development
The enhancer rare germline variation rs548071605 contributes to lung cancer development
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增强子罕见种系变异rs548071605有助于肺癌的发展
DOI：
10.1002/humu.24310
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发表时间：
2021-12
期刊：
影响因子：
3.9
通讯作者：
Sun Yujie
中科院分区：
文献类型：
--
作者：
Wang Xuchun;Cheng He;Yang Yin;Zuo Xianglin;Shao Lipei;Yu Dawei;Yang Nan;Zhang Yu;Li Ruilei;Wang Xinyuan;Shen Bin;Wang Jianying;Shi Xiao;Cao Pingping;Sun Luan;Han Xiao;Sun Yujie
罕见的种系变异导致包括癌症在内的人类复杂疾病的遗传性缺失。由于它们的频率非常低，发现和测试引起疾病的罕见种系变异仍然具有挑战性。22q12.2标记单核苷酸多态性rs17728461与肺癌风险高度相关。在这里，我们在位于22q12.2的p65应答增强子中发现了一个功能性罕见种系变异rs548071605 （a >G）。增强子通过形成染色质环上调白血病抑制因子（LIF）基因，在体外和异种移植小鼠模型中显著促进肺癌细胞增殖。LIF的差异表达及其与患者首次进展生存时间的显著相关性进一步支持了22q-Enh增强子的肺癌驱动作用。重要的是，这种罕见的变异存在于p65结合序列中，通过增加增强子对p65和b细胞淋巴瘤3蛋白（一种辅助p65结合的癌蛋白）的反应性，显著增加了增强子的活性。我们的研究揭示了一种在22q12.2风险区域具有潜在肺癌驱动作用的调节罕见生殖系变异，为研究癌症的“缺失遗传性”提供了有趣的线索，也为识别因果罕见变异提供了有用的实验模型。
Rare germline variations contribute to the missing heritability of human complex diseases including cancers. Given their very low frequency, discovering and testing disease-causing rare germline variations remains challenging. The tag-single nucleotide polymorphism rs17728461 in 22q12.2 is highly associated with lung cancer risk. Here, we identified a functional rare germline variation rs548071605 (A>G) in a p65-responsive enhancer located within 22q12.2. The enhancer significantly promoted lung cancer cell proliferation in vitro and in a xenograft mouse model by upregulating the leukemia inhibitory factor (LIF) gene via the formation of a chromatin loop. Differential expression of LIF and its significant correlation with first progression survival time of patients further supported the lung cancer-driving effects of the 22q-Enh enhancer. Importantly, the rare variation was harbored in the p65 binding sequence and dramatically increased the enhancer activity by increasing responsiveness of the enhancer to p65 and B-cell lymphoma 3 protein, an oncoprotein that assisted the p65 binding. Our study revealed a regulatory rare germline variation with a potential lung cancer-driving role in the 22q12.2 risk region, providing intriguing clues for investigating the "missing heritability" of cancers, and also offered a useful experimental model for identifying causal rare variations.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
14.9
作者：
Tang Z;Li C;Kang B;Gao G;Li C;Zhang Z
通讯作者：
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DOI：
10.2741/3782
发表时间：
2011-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Chen W;Li Z;Bai L;Lin Y
通讯作者：
Lin Y