Single Nucleotide Polymorphisms In DNA Repair And Carcinogen-Metabolizing Genes And Susceptibility To Bladder Cancer

Background & Objective: DNA repair has an essential role in protecting the genomefrom damage by endogenous and environmental agents. Polymorphisms in DNArepair genes may be associated with difference in the repair capacity and mayinfluence an individual's risk of cancer. We preliminarily investigated the associationbetween bladder transitional cell carcinoma(TCC) and single nucleotidepolymorphisms(SNPs) of DNA repair genes(XPC Lys939Gln, XPG His1104Asp andXRCC1 Arg399Gln)among Han-Chinese in Shanghai.Methods: We therefore conducted a case-control study to assess the relationshipbetween single nucleotide polymorphisms in DNA repair genes XPC, XPG andXRCC 1 and Bladder Cancer risk. and we also attempted to assess gene-gene andgene-environmental interactions. A total of 130 primary bladder transitional cellcarcinoma cases and 304 cancer-free controls were recruited and frequency-matched on age and gender status. Genotypes were determined by TaqMan Probe-basedpolymerase chain reaction and DNA sequencing techniques. Adjusted odds ratios(ORs) and their 95% confidence intervals(CIs) were computed to estimate the risk ofbladder transitional cell carcinoma for each genotype. All statistical tests weretwo-side tests.Results: We found that polymorphisms in XPC and XPG but not XRCC1 wereassociated with risk of bladder transitional cell carcinoma.The individuals with bladder transitional cell carcinoma at least having one XPC939Gln had an adjusted OR of 2.80(95%CI=1.79-4.37) compared with noncarriers.Stratification analysis revealed that the increased risk was mainly confined to malewith the adjusted OR of 2.95(95%CI=1.43-6.08) and older individuals(age atdiagnosis≥64 years) with the adjusted OR of 4.17(95%CI=2.14-8.16). In the casegroup, XPC Lys939Gln polymorphisms was associated with tumor stage and tumornumber.Compared with XPG1104Asp/Asp genotype, the His/His and Asp/His genotypewas significantly associated with bladder cancer(adjusted OR=2.62; 95% CI=1.61-4.24). The risk of the(1104His/His+Asp/His)genotype appeared to be morepronounced in females(adjusted OR=2.48;95%CI=1.34-4.60) and in subjects withbladder transitional cell carcinoma who were non-smokers(adjusted OR=4.31; 95%CI=1.19-12.47). In the case group, XPG His1104Asp polymorphisms was notassociated with tumor clinicopathological features. Neither the heterozygote nor thehomozygote variants of XRCC1 Arg399Gln polymorphisms were associated withincreased bladder cancer risk.Smoking increased the risk of developing bladder transitional cell carcinoma,having an adjusted OR of 3.34(95% CI=2.01-5.57). The subjects with heavysmoking and at least having one XPC 939Gln allele had an adjusted OR of 5.54(95%CI=1.86-16.47), compared with noncarriers and heavy smoking,As compared with individuals having no putative high-risk genotypes,individuals with three or more putative high-risk genotypes had a statistical increasedrisk of bladder transitional cell carcinoma. And the adjusted ORs(95%CIs) were1.90(1.13-4.12) for individuals with two high-risk genotypes, 3.59(1.82-9.26) forindividuals with three high-risk genotypes, respectively.Conclusion: The main findings from this case-control study carried out inHan-Chinese in Shanghai were as follows: Smoking may contribute to the bladder transitional cell carcinoma predisposition. DNA repair genes XPC Lys939Gln andXPG Asp1104His single nucleotide polymorphisms may play an important role in thedevelopment of bladder transitional cell carcinoma. The gene-environment interactionbetween XPC Lys939Gln polymorphism and cigarette smoke exposure may also haveeffect on the bladder carcinogenesis. The accumulation of multi-polymorphisms inDNA repair genes has a contribution to the genetic predisposition of bladdertransitional cell carcinoma. Background & Objective: Many carcinogen-metabolizing enzyme genes displaywide ranges of genetic polymorphism. The genetic polymorphism of these enzymesmodulate individual susceptibility to certain disease. There are notable deviations onthe population frequency of carcinogen-metabolizing gene polymorphism amongdifferent ethnic groups and regional resident population. We preliminarilyinvestigated the association between bladder transitional cell carcinoma(TCC) andsingle nucleotide polymorphisms(SNPs) of carcinogen-metabolizing enzymegenes(CYP2C9~*3, CYP2C19~*2, CYP2C19~*3, CYP2D6~*10, CYP3A4~*18 andCYP3A5~*3)among Han-Chinese in Shanghai.Methods: We therefore conducted a case-control study to assess the relationshipbetween single nucleotide polymorphisms in xenobiotic metabolism genesCYP2C9~*3, CYP2C19~*2, CYP2C19~*3, CYP2D6~*10, CYP3A4~*18 and CYP3A5~*3and Bladder Cancer risk. and we also attempted to assess gene-gene andgene-environmental interactions. A total of 130 primary bladder transitional cellcarcinoma cases and 304 cancer-free controls were recruited and frequency-matchedon age and gender status. Genotypes were determined by TaqMan Probe-basedpolymerase chain reaction. Adjusted odds ratios(ORs) and their 95% confidenceintervals(CIs) were computed to estimate the risk of bladder transitional cellcarcinoma for each genotype. All statistical tests were two-side tests.Results: The distribution of genotypes of these CYP polymorphisms geneticvariants in cases and controls was consistent with Hardy-Weinberg equilibrium. Usinglogistic regression adjusting for smoking, gender and age, neither the heterozygotenor the homozygote variants of CYP2C9~*3, CYP2C19~*2,, CYP2D6~*10, CYP3A4~*18and CYP3A5~*3 polymorphisms were associated with increased bladder cancer risk(adjusted odds ratio [95% confidence interval] for heterozygote 1.02[0.61-1.68],0.85[0.47-1.54], 1.09[0.67-1.77], 1.12[0.67-1.86] and 0.58[0.24-1.38], respectivelyand homozygote variant, 1.02[0.63-1.63], 0.98[0.65-1.59], 1.50[1.00-2.25],0.92[0.54-1.57] and 0.96[0.65-1.40]).The CYP2C19~*3 polymorphisms was notassociated with bladder cancer risk either(adjusted OR:1.01; 95% CI=0.42-2.45).Moreover, we did not find any significant interaction between these CYPpolymorphisms and environmental exposure to cigarette smoking. As compared with individuals having one putative high-risk genotypes,individuals with two or more putative high-risk genotypes had not a statisticalincreased risk of bladder transitional cell carcinoma.Conclusion: The main findings from this case-control study carried out inHan-Chinese in Shanghai were as follows: the single nucleotide polymorphisms(SNPs) of CYP2C9~*3, CYP2C19~*2, CYP2C19~*3, CYP2D6~*10, CYP3A4~*18 andCYP3A5~*3 may not influence the risk of bladder transitional cell carcinoma. Background & Objective: Accumulating evidence shows that most cancers arecaused by interactions of many low-penetrance susceptibility genes. In this study, weinvestigated the association between risk of bladder transitional cell carcinoma andsingle nucleotide polymorphisms(SNPs) in multiple loci in a case-control study consisted of 130 patients and 304 cancer-free controls.Methods: The functional SNPs investigated were XPC Lys939Gln, XPGHis1104Asp, XRCC1Arg399Gln, CYP2C9~*3, CYP2C19~*2, CYP2C19~*3,CYP2D6~*10, CYP3A4~*18 and CYP3A5~*3. Traditional unconditional logisticregression model was used to evaluate the effect of single SNP alone in chapter oneand chapter two. In this chapter, multifactor-dimensionality reduction(MDR) wasapplied to examine the interactions between these 9 SNPs interactions.Results: It was found that, among these SNPs, MDR analysis revealed that the XPCLys939Gln and XPG His1104Asp SNPs displayed significant interaction in risk of thebladder cancer. Moreover, two sets of polymorphisms were found to nteract, whichincreased the risk of bladder cancer.Conclusion: Our results support the hypothesis that bladder cancer is a complexdisease resulting from the interactions of low-penetrance genes and MDR seems to bea useful analytical tool for complex genetic diseases.