Association Between Two Single Nucleotide Polymorphisms Rs11892031 ?rs401681and Bladder Cancer Risk And Prognosis

Objective We aimed to validate the association between two single nucleotide polymorphisms(rs11892031 and rs401681) and bladder cancer risk in a Chinese population by genome-wide association studies(GWAS) as the clues, and to explore the potential accoations of the SNPs with grade/stage and prognosis in bladder cancer.Materials and Methods All subjects were of Chinese Han descent. Three-hundred and sixty-seven bladder cancer patients were selected from the Second Hospital of Tianjin Medical University, Tianjin, northern China. All cases were patients newly diagnosed with histologically confirmed urothelial carcinoma of bladder. As control group, 420 sexand age-matched healthy subjects without previous history of cancer were enrolled during the same period of time. A 4 m L peripheral venous blood sample was obtained for each subject after the interview. Genotyping of the SNPs performed using ligation detection reaction-PCR(LDR-PCR) and ten percent of masked samples were randomly selected for confirmation with direct sequencing. The clinical data of the patients with bladder cancer in detail summary and complete follow-up.Statistical analysis Hardy–Weinberg equilibrium was evaluated by a goodness-of-?2 test to compare the observed genotype frequencies with the expected ones of the controls. Differences between cases and controls in demographic characteristics, risk factors and frequencies of allele and genotype of each SNP were evaluated by two-sided ?2test(for categorical variables) or Student's t-test(for continuous variables). Unconditional multivariate logistic regression was applied to calculate odds ratios(ORs) and 95%confidence intervals(CIs) to estimate the association between the polymorphisms and susceptibility of bladder cancer, with adjustment for age, sex and smoking status. The heterogeneity between ORs of subgroups was estimated using the ?2-based Q-test.The survival curves for patients with different genotype were estimated using the Kaplan-Meier method, and Log-rank test was conducted to evaluate the statistically significance. All analyses were performed using SPSS(version 19.00) and all testswere two sided, P<0.05 was considered significant.Results1. Characteristics of the study participants There was no significant difference in the mean age between cases and controls.No significant difference in age or sex distribution was observed between cases and controls. However, the distribution of smokers in cases was significantly different from that in controls(P<0.001), with the cases having much higher percentage of former smokers(31.41%) than the controls(15.95%) andconsequently less never smokers than the controls. The genotype distributions for SNP rs11892031 and rs401681 in controls were in accordance with the predicted from the Hardy–Weinberg equilibrium model(P>0.05).2. Association between rs11892031 polymorphism and bladder cancer susceptibility Compared to the A allele of rs11892031, the C allele implicated a significantly increased risk for bladder cancer susceptibility(adjusted OR=0.28, 95%CI=0.09-0.82,P=0.020). Our analysis showed that the AC genotype was associated with decreased bladder cancer risk(adjusted OR, 0.27; 95% confidence interval(CI), 0.09–0.81; P=0.019) when the AA genotype served as reference.3. Association between rs11892031 polymorphism and tumor grade/stage We further assessed the association between rs11892031 and tumor grade and stage of bladder cancer. No heterogeneity in ORs between tumor grades or stages was observed for rs11892031(P>0.05), indicating that rs11892031 did not associate with bladder tumor grade and stage in this study population.4. Association between rs401681 polymorphism and bladder cancer susceptibility The C allele of rs401681 was found to be associated with higher risk of bladder cancer(adjusted OR=1.26, 95%CI=1.02-1.57, P=0.035) compared to the T allele. The combined group(CT/CC genotype) had a significant association with increased bladder cancer risk as well(adjusted OR, 1.79; 95%CI, 1.10–2.91; P=0.020),compared with TT genotype.5. Association between rs401681 polymorphism and tumor grade/stage Similar to the case of rs11892031, no heterogeneity in ORs between the bladder cancer categories was detected for rs401681(P>0.05). Thus, the association ofrs401681 with bladder tumor grade and stage was not supported in our case-control study population.6. Association of rs11892031 and rs401681 polymorphisms with prognosis for bladder cance Stratified analysis results showed that no significant statistical difference was found in tumor recurrence and progression in patients with bladder cancer for rs11892031(P>0.05); On the contrary, compared with CT/CC genotype, rs401681 TT genotype plays a protective role of bladder cancer recurrence(P=0.011).Kaplan–Meier curves showed the significant differences in the recurrence-free survival between the TT genotype and CT/CC genotype, with a log-rank P value of0.020.Conclusions The rs11892031 and rs401681 polymorphisms are associated with risk of bladder cancer in a northern Chinese population, and there is no significant association between rs11892031/rs401681 and tumor stage/grade in this population; rs401681 shows significant differences in the distribution of genotype, which pointed the SNP could be a prognostic factor in bladder cancer.