Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.
Gut. 2020 Apr;69(4):641-651. doi: 10.1136/gutjnl-2019-318760. Epub 2019 Aug 5.
Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development.
We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies.
The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of , resulting in a reduced promoter activity and lower expression. The knockout of promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of , while the knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10) and 4q28.1 (OR=1.14, p=3.33×10) were associated with GC risk.
We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of at 5p13.1 and at 10q23.33 in gastric tumourigenesis.
虽然有一部分遗传位点与胃癌（GC）风险相关，但其中的机制在很大程度上尚不清楚。我们旨在发现新的易感性基因，并阐明其在 GC 发展中的作用机制。
我们对四项全基因组关联研究（GWASs）进行了荟萃分析，共纳入 3771 例病例和 5426 例对照。在靶向测序和功能注释之后，我们进行了体外和体内实验以验证遗传变异和候选基因的功能。此外，我们选择了 33 个有前途的变异在另外五个研究的 7035 例病例和 8323 例对照中进行了两阶段复制。
GWASs 的荟萃分析在 p<5×10 处确定了三个与 GC 风险相关的位点 1q22、5p13.1 和 10q23.33，在 p<0.05 处复制了七个已知的位点。在 5p13.1 上，风险 rs59133000[C]等位基因增强了 NF-κB1（核因子 kappa B 亚单位 1）与 启动子的结合亲和力，导致启动子活性降低和表达水平降低。在裸鼠中，敲除 促进了 GC 细胞增殖和异种移植肿瘤生长。在 10q23.33 上，完全连锁不平衡的 rs3781266[C]和 rs3740365[T]风险等位基因分别创建了 POU2F1 和 PAX3 的结合基序，导致 的增强子活性和表达增加，而 敲低则抑制了 GC 细胞生长。此外，在 3q11.2（OR=1.21，p=4.56×10）和 4q28.1（OR=1.14，p=3.33×10）上发现了两个与 GC 风险相关的新位点。
我们在中国人群中确定了 12 个与 GC 风险相关的位点，并阐明了 5p13.1 上的 和 10q23.33 上的 在胃肿瘤发生中的作用机制。
