Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer
Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer
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16p13 风险变异对 lncRNA GCLET 的远程调节潜在的胃癌遗传易感性
DOI：
10.1126/sciadv.aay5525
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发表时间：
2020-05-01
期刊：
影响因子：
13.6
通讯作者：
Zhang, Zhengdong
中科院分区：
文献类型：
--
作者：
Du, Mulong;Zheng, Rui;Zhang, Zhengdong
该综合分析策略确定了胃癌病因的遗传和表观遗传生物标志物。胃肿瘤发生过程中易感位点的生物学效应很少报道。我们对18852名个体进行了大规模的跨祖先遗传研究，发现16p13位点的潜在致病变异rs3850997 T>G与胃癌风险降低显著相关[优势比(OR) = 0.87, 95%可信区间(CI) = 0.83 ~ 0.91, P = 2.13 × 10−9]。这种风险效应是通过映射的长链非编码RNA GCLET（胃癌低表达转录本；or间接= 0.987,95% CI = 0.975 ~ 0.999, P = 0.018）介导的。机制上，rs3850997通过影响CTCF的结合亲和力对GCLET发挥等位基因特异性的远程调控作用。此外，GCLET通过与miR-27a-3p竞争而增加FOXP2的表达，这种调节显著影响了体外、体内和临床胃癌表型。这些发现强调了癌症的遗传功能及其对病因和病理的影响。
The integrated analytical strategy identified both genetic and epigenetic biomarkers for gastric cancer etiology. The biological effects of susceptibility loci are rarely reported in gastric tumorigenesis. We conducted a large-scale cross-ancestry genetic study in 18,852 individuals and identified the potential causal variant rs3850997 T>G at 16p13 significantly associated with a decreased risk of gastric cancer [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.83 to 0.91, P = 2.13 × 10−9]. This risk effect was mediated through the mapped long noncoding RNA GCLET (Gastric Cancer Low-Expressed Transcript; ORindirect = 0.987, 95% CI = 0.975 to 0.999, P = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on GCLET by affecting the binding affinity of CTCF. Furthermore, GCLET increased FOXP2 expression by competing with miR-27a-3p, and this regulation remarkably affected in vitro, in vivo, and clinical gastric cancer phenotypes. The findings highlight the genetic functions and implications for the etiology and pathology of cancers.