Structural and numeric centrosome aberrations can induce chromosome segregation errors and promote tumor development and progression. We systematically evaluated associations of 19,603 single nucleotide polymorphisms (SNPs) across 136 centrosome-related genes with gastric cancer (GC) risk using four GWAS datasets with a total of 3771 cases and 5426 controls. We identified two loci at 15p13.3 and 7q11.23 significantly associated with GC risk, whose risk alleles were correlated with increased mRNA expression of CEP72 (P = 7.30 × 10^–4) and YWHAG (P = 1.60 × 10^–3), respectively. Dual-luciferase reporter assays confirmed that the risk T allele of rs924607 at 15p13.3 significantly increased a promoter activity of the reporter gene, leading to a higher CEP72 expression level. At 7q11.23, the risk haplotype of rs2961037 [G]-rs2961038 [G] significantly elevated an enhancer activity and the expression of YWHAG. Both the mRNA and protein levels of CEP72 and YWHAG were overexpressed in GC tumor tissues compared with peritumor tissues and overexpression of either gene showed an unfavorable prognosis of GC patients. Moreover, knockdown of either CEP72 or YWHAG inhibited GC cell proliferation, migration and invasion and promoted GC cell apoptosis. The genes coexpressed with CEP72 or YWHAG in GC tumor tissues were enriched in the Ras signaling pathway, which was confirmed that knockdown of either one decreased the expression of cyclin D1 but increased the expression of p21 and p27. In conclusion, genetic variants at 15p13.3 and 7q11.23 may confer GC risk via modulating the biological functions of CEP72 and YWHAG, respectively, suggesting the importance of centrosome-regulated genes in GC development.

结构和数字中心体畸变会导致染色体分离错误并促进肿瘤的发展和进程。我们使用四个GWAS数据集（共3771个病例和5426个对照）系统地评估了136个中心体相关基因中的19,603个单核苷酸多态性（SNP）与胃癌（GC）风险的关联。我们在15p13.3和7q11.23处确定了两个与GC风险显着相关的基因座，它们的风险等位基因与CEP72（P  = 7.30×10 ^–4）和YWHAG（P  = 1.60×10 ^–3）的mRNA表达增加相关。）， 分别。双重荧光素酶报告基因测定证实，在15p13.3处rs924607的风险T等位基因显着增加了报告基因的启动子活性，从而导致更高的CEP72表达水平。在7q11.23，rs2961037 [G] -rs2961038 [G]的风险单倍型显着提高了增强子活性和YWHAG的表达。与胃癌组织相比，GC肿瘤组织中CEP72和YWHAG的mRNA和蛋白水平均过表达，并且任一基因的过表达都表明GC患者的预后不良。此外，击倒CEP72或YWHAG抑制GC细胞增殖，迁移和侵袭并促进GC细胞凋亡。在GC肿瘤组织中与CEP72或YWHAG共表达的基因在Ras信号通路中富集，这证实了两者的组合均降低了细胞周期蛋白D1的表达，但增加了p21和p27的表达。总之，位于15p13.3和7q11.23的遗传变异可能分别通过调节CEP72和YWHAG的生物学功能而赋予GC风险，提示中心体调节基因在GC发育中的重要性。