The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression

作者：Lipei Shao, Xianglin Zuo, Yin Yang, Yu Zhang, Nan Yang, Bin Shen, Jianying Wang, Xuchun Wang, Ruilei Li, Guangfu Jin, Dawei Yu, Yuan Chen, Luan Sun, Zhen Li, Qiaofen Fu, Zhibin Hu, Xiao Han, Xin Song, Hongbing Shen, Yujie Sun · 发表于：Genome biology · 年份：2019 · DOI：10.1186/s13059-019-1696-1 · 被引用次数：37 · 研究领域：DNA Repair Mechanisms、Genomics and Chromatin Dynamics、Cancer-related Molecular Pathways

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 ...