报道称蛋白质WWOX通过与mTOR和DNA修复途径的相互作用参与了癌症进展。我们先前报告了某些mTOR和DNA修复途径的单核苷酸多态性（SNP）与胃癌（GCa）患者生存率的显著关联。我们假设WWOX基因中的遗传变异可以预测GCa患者的生存率。通过从我们的正在进行的全基因组关联研究中提取来自东部中国人群的796例GCa患者的WWOX遗传变异，我们确定了51个1913个SNP与GCa患者的生存率显著相关，通过了误报概率检验。特别地，内含子变异rs9922483，G>T的改变，与GCa患者的死亡风险增加21%相关（HR=1.21，95% CI=1.04-1.42，P=.015）。通过生物信息学分析，预测该位点参与潜在增强子。基因型与表型相关分析显示，rs9922483 G>T改变导致WWOX表达下降。机制上，rs9922483位点可能与WWOX启动子发生远程相互作用，并且G>T改变抑制了WWOX启动子在荧光酶报告系统中的转录活性。尤其是，G>T改变对NR3C1结合产生了等位基因特异性负效应，并且NR3C1促进了GCa细胞中WWOX的表达。进一步的功能分析表明，敲低WWOX可增加GCa细胞的增殖、迁移和入侵。总之，WWOX的遗传变异可能通过对WWOX表达的远程调节效应调节中国GCa患者的生存率。我们的结果强调了遗传变异对基因和GCa患者生存调控的顺式调控效应。© 2023 UICC.

The protein WWOX was reported to be involved in cancer progression via interaction with mTOR and DNA repair pathway. We previously reported noteworthy association of some single nucleotide polymorphisms (SNPs) in mTOR and DNA repair pathways with gastric cancer (GCa) patients' survival. We hypothesized that genetic variants in WWOX gene could predict the survival of GCa patients. By extracting WWOX genetic variants from our ongoing genome-wide association study including 796 GCa patients from an Eastern Chinese population, we identified 51 out of 1913 SNPs to be significantly associated with survival of GCa patients, which passed the false positive probability tests. In particular, the intronic variant rs9922483, a G>T change, was associated with 21% increased death risk for GCa patients (HR = 1.21, 95% CI = 1.04-1.42, P = .015). This locus was predicted to be involved in potential enhancer by bioinformatics analysis. Genotype-phenotype correlation analysis revealed decreased expression of WWOX by rs9922483 G>T change. Mechanistically, rs9922483 locus may exhibits long-range interaction with WWOX promoter, and the G>T change inhibited the transcriptional activity driven by WWOX promoter in luciferase reporter system. Especially, the G>T change had an allele-specific negative effect on NR3C1 binding, and NR3C1 promoted the expression of WWOX in GCa cells. Further functional analysis indicated an increase in proliferation, migration and invasion of GCa cells by knockdown of WWOX. In conclusion, WWOX genetic variants may modulate survival of Chinese GCa patients by exerting remote regulatory effect on WWOX expression. Our results highlight the cis-regulatory effect of genetic variants on genes and survival modulation for GCa patients.© 2023 UICC.