The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression
The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression
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13q12.12 中 p53 响应增强子的遗传变异通过减弱 TNFRSF19 表达而赋予肺癌风险
DOI：
10.1186/s13059-019-1696-1
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发表时间：
2019-05-24
期刊：
影响因子：
12.3
通讯作者：
Sun, Yujie
中科院分区：
文献类型：
--
作者：
Shao, Lipei;Zuo, Xianglin;Sun, Yujie
背景：遗传因素有助于肺癌的风险，但其机制尚不清楚。确定GWAS命中在癌症中的生物学后果是阐明癌症遗传机制的一个有前途的策略。13q12.12区域rs753955（A>G）单核苷酸多态性与中国人群肺癌风险高度相关。在这里，我们系统地研究了13q12.12风险位点的生物学意义和潜在的机制在体外和体内。结果：我们描述了一种新的p53响应增强子与肺组织细胞特异性在一个49 kb的高连锁不平衡块的rs753955。该增强子含有3个高度连锁的常见遗传变异（rs17336602、rs4770489和rs34354770）和6个靠近或位于变异之间的p53结合序列。该增强剂通过染色质成环上调TNFRSF19，有效保护正常肺细胞系免受肺致癌物NNK诱导的DNA损伤和恶性转化。这些变化通过影响其p53反应而显著削弱增强子活性，特别是当细胞暴露于NNK时。117例中国人NSCLC样本的表达数量性状位点分析和GTEx数据支持突变增强子等位基因对TNFRSF19靶基因的体内效应。TNFRSF19的差异表达及其与肿瘤TNM分期和患者生存率的统计学显著相关性表明TNFRSF19在肺癌中的抑制作用。结论：本研究提供了证据表明，13q12.12的遗传变异如何有助于肺癌的风险，突出了致癌物应激下肺细胞中p53应答增强子介导的TNFRSF19激活的保护作用。
Background:Inherited factors contribute to lung cancer risk, but the mechanism is not well understood. Defining the biological consequence of GWAS hits in cancers is a promising strategy to elucidate the inherited mechanisms of cancers. The tag-SNP rs753955 (A>G) in 13q12.12 is highly associated with lung cancer risk in the Chinese population. Here, we systematically investigate the biological significance and the underlying mechanism behind 13q12.12 risk locus in vitro and in vivo.Results:We characterize a novel p53-responsive enhancer with lung tissue cell specificity in a 49-kb high linkage disequilibrium block of rs753955. This enhancer harbors 3 highly linked common inherited variations (rs17336602, rs4770489, and rs34354770) and six p53 binding sequences either close to or located between the variations. The enhancer effectively protects normal lung cell lines against pulmonary carcinogen NNK-induced DNA damages and malignant transformation by upregulating TNFRSF19 through chromatin looping. These variations significantly weaken the enhancer activity by affecting its p53 response, especially when cells are exposed to NNK. The effect of the mutant enhancer alleles on TNFRSF19 target gene in vivo is supported by expression quantitative trait loci analysis of 117 Chinese NSCLC samples and GTEx data. Differentiated expression of TNFRSF19 and its statistical significant correlation with tumor TNM staging and patient survival indicate a suppressor role of TNFRSF19 in lung cancer.Conclusion:This study provides evidence of how the inherited variations in 13q12.12 contribute to lung cancer risk, highlighting the protective roles of the p53-responsive enhancer-mediated TNFRSF19 activation in lung cells under carcinogen stress.