Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Sci Adv. 2020 May 20;6(21):eaay5525. doi: 10.1126/sciadv.aay5525. eCollection 2020 May.
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, = 2.13 × 10]. This risk effect was mediated through the mapped long noncoding RNA (; OR = 0.987, 95% CI = 0.975 to 0.999, = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on by affecting the binding affinity of CTCF. Furthermore, increased 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.
易感性基因座的生物学效应在胃癌发生中很少报道。我们在 18852 个人中进行了大规模的跨种族遗传研究，鉴定出与胃癌风险降低显著相关的潜在因果变异 rs3850997 T>G（优势比 [OR] = 0.87，95%置信区间 [CI] = 0.83 至 0.91， = 2.13×10）。这种风险效应是通过映射到的长非编码 RNA （lncRNA）介导的（OR = 0.987，95%CI = 0.975 至 0.999， = 0.018）。从机制上讲，rs3850997 通过影响 CTCF 的结合亲和力，对 发挥了等位基因特异性的长程调控作用。此外，通过与 miR-27a-3p 竞争，增加了 的表达，这种调控对体外、体内和临床胃癌表型有显著影响。这些发现突出了遗传功能及其对癌症病因和病理学的意义。
