Association Between Genetic Polymorphisms Of XRCC6 And ERCC4 And Susceptibility Of Bladder Cancer

Background and ObjectiveBladder cancer is a common malignant tumor. In the wordwide, bladder cancer is the second common cancer after prostate cancer in Urology malignant tumors. But the bladder cancer is the first common cancer in China. The tumorigenesis of bladder cancer is complex, multi-factor, multi-step process of pathological changes, the exact etiology and pathogenesis are not entirely clear. The occurrence of bladder cancer may be associated with smoking, eating habits, environmental carcinogens and so on. Physical and chemical carcinogens in the environment factors and endogenous reactive oxygen species can cause cellular DNA damage, if such damage can not be repaired accurate and timely, or beyond the body's repair capacity, the damage may lead to tumor formation. The results show that DNA repair gene polymorphism is an important decision based on individual genetic susceptibility. XRCC6 and ERCC4/XPF play important roles in the repair of DNA damage. Some studies show that XRCC6 and ERCC4/XPF gene polymorphisms have closed relations with breast cancer, lung cancer, head and neck cancer susceptibility. However, there is no information in the relation of genetic polymorphisms of XRCC6 and ERCC4/XPF with bladder cancer. The aim of our study is to elucidate whether some polymorphisms of XRCC6 c.-1310 C>G and ERCC4 Arg415Gln genes might be associated with the risk of bladder cancer. The potential interactions of these DNA repair enzymes with the risk factors such as smoking tobacco are also explored.Materials and Methods SubjectsThe study design was approved by the Committee on Human Research of Zhengzhou University. The study population consisted of a series of bladder cancer patients and non-cancer controls admitted to the department of urology, the first affiliated hospital of Zhengzhou University and the department of urology, the people hospital of Henan Province from February of 2006 to December of 2009. The study subjects gave informed consent prior to participation in the study. Patients who were diagnosed as incident bladder cancer cases with histopathological confirmation, and from whom a peripheral blood sample was drawn and selected as cases. Controls who were individuals with no present or previous history of bladder cancer or other tumors were simultaneously recruited in the same hospitals. The two groups were collected from Han ethnic population in Henan province. The rate distribution of age, gender in two groups is balanced, and they were comparable with each other.Epidemiological InvestigationInformation on demographic characteristics, education, marital status, family history of bladder cancer in the first and second relatives, occupational exposure history, life style including tobacco smoking, and well-done meat consumption, were collected by trained interviewers using a structured questionnaire.GenotypingGenotyping of XRCC6 c.-1310 C>G and ERCC4 Arg415Gln variants was conducted by the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method. PCR products were detected by agarose gel electrophoresis. Alleles and genotypes were defined by fragments in agarose gel.Statistical AnalysisStatistical analysis was conducted using the package SPSS 13.0 for Windows. Chi-square was used to compare the distribution of genotypes and single alles in cases and controls. The association between environmental risk factors and bladder cancer was studied by unconditional logistic regressive analysis. An odds (OR) and 95% confidence interveral (95%CI) were also caculated, P-value<0.05.Results1.The Detection of XRCC6 and ERCC4 genetic equilibriumThe distribution of the XRCC6 and ERCC4 allele frequencies among control subjects was in Hardy-Weinberg equilibrium.2.Association between XRCC6 c.-1310 C>G genotypes or alleles and susceptibility of bladder cancerIn the bladder cancer subjects, the frequencies of the C/C, C/G and G/G genotypes were 62.94%(197/313),32.27%(101/313) and 4.79%(15/313), respectively. In the control subjects, the frequencies of the C/C, C/G and G/G genotypes were 73.70%(227/308),23.05%(71/308) and 3.25%(10/308), respectively.The frequency of XRCC6 c.-1310 C>G variant allele was significantly higher in the case subjects (37.06%) in controls (26.30%)(P<0.05, OR=1.65,95%CI 1.17-2.32).3.Association between ERCC4 Arg415Gln genotypes or alleles and susceptibility of bladder cancerIn the bladder cancer subjects, the frequencies of the G/G, G/A and A/A genotypes were 89.46%(280/313),9.26%(29/313) and 1.28%(4/313), respectively. In the control subjects, the frequency genotypies of the G/G, G/A and A/A genotypes were 87.01%(268/308),12.01%(37/308) and 0.98%(3/308), respectively.The difference of distribution frequency of ERCC4 Arg415Gln genotypes was not significant between case group and control group (P>0.05).4.Smoking factor and bladder cancerCompared with the nonsmokers, smokers have a higher risk to bladder cancer, which is 1.86 times as high as nonsmokers. (OR=1.86,95%CI 1.35-2.56).5.Interaction of XRCC6 and ERCC4 genotypes and smoking fator to susceptibility of bladder cancerThe smokers with XRCC6 c.-1310 C>G variant genotypes showed increased risk of bladder cancer compared with those with wild genotype (P<0.05, OR=2.02, 95%CI 1.81-3.46). The nosmokers with variant genotypes have no significant difference with wild genotypes(P>0.05). It indicates that the gene polymorphisms and smoking behavior have interaction in the occurrence of bladder cancer process.The ERCC4 Arg415Gln genotype was no significant difference among the smokers and the nonsmokers(P>0.05). It indicates that the ERCC4 Arg415Gln gene polymorphisms and smoking behavior have no interaction in the occurrence of bladder cancer process.6.XRCC6 and ERCC4 genotypes and pathological grade and clinical stage of bladder cancerFor the XRCC6 c.-1310 C>G and ERCC4 Arg415Gln genotypes, there was no association between the XRCC6 and ERCC4 polymorphisms and pathological grade and clinical stage of bladder cancer.Conclusions1. The genetic polymorphism of XRCC6 c.-1310 C>G is associated with the susceptibility of bladder cancer, it can increase the bladder cancer risk. However, there is no relation between polymorphisms of ERCC4 Arg415Gln gene and bladder cancer.2. XRCC6 c.-1310 C>G gene polymorphism and smoking behavior have interaction in the occurrence of bladder cancer process. Smokers possessing the variant genotype have higher risk for bladder cancer.3. There is no association between the XRCC6 and ERCC4 polymorphisms and pathological grade and clinical stage of bladder cancer.