Ctnnb1 Polymorphisms And The Survival Of Gastric Cancer: A Molecular Epidemiology Study

Gastric cancer is the second most common cancer in incidence and the fourth mortality worldwide. Also, gastric cancer is the second most common cancer in China, and more than one-thirds of gastric cancer cases occur in China. Gastric cancer remains a highly lethal disease in both man and woman, which remains a significant cancer burden in China. Similarly, different gastric cancer patients with identical stage always have different survival time even under equal treatment. Many studies have demonstrated that genetic variations, particularly the single nucleotide polymorphisms (SNPs), play an important role in cancer development and prognosis. CTNNB1 gene, as an important member of the Wnt pathway, which is closely related to the embryonic development and tumor formation, is associated with tumor formation, invasion and metastasis through participation in cells adhesion and signaling. Invasion and metastasis are important steps in tumor progression and usually associated with poor prognosis. We hypothesized that the polymorphisms of CTNNB1 gene are associated with the gastric cancer survival and can be used for the prediction of clinical outcome of gastric cancer. A total of 1022 gastric cancer cases diagnosed with pathologic examination and undergone a surgical operation between January 1, 1999 and December 31, 2006 were enrolled as the observated subjects at Yixing People's Hospital, Yixing, China. As a result, 1016 patients were successfully followed up in March 2009, in which 944 cases had completely biological samples. The genomic DNA was extracted from paraffin-embedded tumor by phenol-chloroform. From HapMap database, 5 tagSNPs (tagging SNPs,tSNPs) (i.e., rs1798802, rs1880481, rs4135385, rs11564475 and rs2293303) of CTNNB1 gene were selected. Survival curves were plotted by Kaplan-Meier method and the differences of survival time were tested by Log-rank test. Univariate or multivariate Cox regression models were fitted to estimate the hazard ratios (HRs), and 95% confidence intervals (CIs) for the associations and the effect of CTNNB1 polymorphisms and the survival of gastric cancer.In this study we observed that tumor size (≥5.0 cm), the type of organization (diffuse type), the depth of tumor invasion (≥T3), lymph node metastasis (N1 and N2), distant metastasis, clinical stage (≥IIIA) and surgery programs (palliative surgical resection and short circuit) are all of poor prognosis factors (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P = 0.004, P < 0.001, P = 0.003, respectively). Univariate Cox regression analysis revealed that patients carrying the CTNNB1 rs4135385 AG/AA genotypes had a significantly 20% decreased death risk (HR = 0.80, 95% CI = 0.67-0.97) compared with those with the rs4135385 GG genotype, and this protective effect was more pronounced in elderly patients (> 62 years), non-cardia carcinoma, larger tumor diameter (≥5.0 cm), lymph node metastasis in the N1 stage, distant metastasis and clinical staging in stage III (including IIIA, and IIIB). Finally, lymph node metastasis (N1 and N2), surgery program (palliative surgical resection and short circuit) and CTNNB1 rs4135385 G>A polymorphism were selected into the Cox regression model. In non-cardia carcinoma patients, the protective effect of AG/AA genotypes in elderly men (> 62 years), larger tumor diameter (≥5.0 cm), and clinical staging in stage III with radical resection and postoperative chemotherapy also became more apparent. In cardia carcinoma patients, the protective effect of AG/AA genotypes only showed in the patients with lymph node metastasis in N2 stage. For the intestinal type patients, the AG/AA genotypes were more prominent associated with improved survival in the patients with distant metastasis, clinical stage at III and radical resection compared with those with GG genotype and the death risk decreased by 39% (HR = 0.61, 95% CI = 0.42-0.86 ), 51% (HR = 0.49, 95% CI = 0.27-0.90) and 24% (HR = 0.76, 95% CI = 0.55-1.06). The diffuse type of gastric cancer patients carrying AG/AA genotype with≥5.0 cm tumor diameter and women had significantly 43% (HR = 0.57, 95% CI = 0.33-0.96) and 39% (HR = 0.61, 95% CI = 0.42-0.86) decreased death risk.Our results indicated that for surgically resectable gastric cancer patients, curative radical surgery should be performed to improve survival. Palliative resection surgery and short circuit can not prolong the survival time. The CTNNB1 rs4135385 G> A polymorphism, as an independent risk factor, may be a prognostic biomarker for non-cardia gastric carcinoma and it may prevent the occurrence and development of non-cardia gastric carcinoma.