Association Of VEGF Gene Variants With Gastric Cancer Risk And Expression Of VEGF And COX-2 In Gastric Cancer Tissues

Objective To study the correlation between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) gene and susceptibility of gastric cancer in Anhui Region of China, to investigate the relationships among these SNPs in VEGF gene and clinicalpathological parameters as well as expression of VEGF and cyclooxygenase -2 (COX-2) in gastric cancer tissues and to explore the potential pathogenesis of gastric cancer.Methods Distribution modalities of 14 VEGF gene variants in 311 patients with gastric cancer and 425 controls from Anhui Province were genotyped by using Gene sequencing instrument (Sequenom). Expressions of VEGF and COX-2 in 238 tissue samples of gastric cancers and 30 samples of adjacent noncancerous tissues from the patients were accordingly detected by tissue microarray-based immunohistochemistry.Results We found that there were no significant differences among genotypes, allele and haplotype distributions of the 14 VEGF polymorphisms between the cases and the controls. However, we observed that the VEGF rs833070GA and the rs3025007CT genotypes significantly decreased the risk of gastric carcinoma (P=0.028, AOR =0.71, 95%CI =0.52-0.96; P=0.034, AOR =0.71, 95%CI=0.52-0.97), compared with the GG and CC genotypes, respectively; while the VEGF rs3025039TT appearred a weak trend to increase the risk of this disease (P=0.060 , AOR =2.61, 95%CI=0.96-7.10). Furthermore, we revealed significant correlations between SNPs of VEGF gene and parts of clinicalpathological parameters of gastric cancers, for example, the VEGF rs3024994CT genotype and male (P=0.009, OR=0.35, 95%CI=0.16-0.76), the rs3025021C/T polymorphism and tumor size (P=0.025), the rs3025039CT genotype and tobacco smoking (P=0.026, OR=1.82, 95%CI=1.07-3.09), the VEGF rs3025030G/C polymorphism and tumor location (P=0.023), the CG genotype of rs3025030GC and both tobacco smoking (P=0.001, OR=2.45, 95%CI=1.45-4.14) and alcohol drinking (P=0.006, OR=2.04, 95%CI=1.22-3.39), respectively. Moreover, AA genotype (P=0.050, OR=0.39, 95%CI=0.15-1.00) and A alleles (P=0.024, OR=0.64, 95%CI=0.43-0.94) of the VEGF rs833052 significantly reduced the VEGF protein expression, respectively. Instead, T allele of the VEGF rs3025007 increased the VEGF expression (P=0.017, OR=1.70, 95%CI=1.10-2.61) when compared to the C alleles. At the protein level, significant expressions of both VEGF and COX-2 (62.6% and61.8%, respectively) occurred in gastric cancers, compared to the adjacent tissues (26.7% with P=0.000 and 36.7% with P=0.008, respectively). There were statistically significant correlations of the expressions of VEGF and COX-2 to biological behaviors of gastric cancers in clinical TNM stage, tumor size, invasive depth, lymph node metastasis, clinical stage (only VEGF) and histological type (only COX-2) (P=0.001-0.05), respectively. The VEGF expression displayed a significant association with COX-2 (rs= 0.178, P=0.006).Conclusion The VEGF rs833070GA and rs3025007CT genotypes would be two protective indexes for gastric cancer; while VEGF rs3025039TT might be a risk factor for this disease. The significant correlations between SNPs of VEGF and clinicalpathological parameters in this study included that the rs3024994CT genotype might be a protective index for male; the rs3025021CT and rs3025030GC genotypes would be associatde with invension of tumor; rs3025030GC and rs3025039CT increased the risk of gastric cancer; the AA genotype and A allele of rs833052 decreased the risk of this tumor; while T allele of the VEGF rs3025007 increased the risk of this disease. The evidence that VEGF and COX-2 overexpressed in tumor tissue and associated with the malignant clinicalpathological features suggested that the two proteins strongly associated with the invasion of gastric cancer. The positive correlation with VEGF and COX-2 implies that they might play a synergistic role in the progress of gastric cancers.