Genetic Variants Of Ape1 Gene Contribute To Susceptibility To Cervical Cancer And Their Mechanisms

Objective: Apurinic/apyrimidinic endonuclease-1 (APE1) is an essential enzyme in the base excision repair pathway, which is the primary mechanism for the repair of DNA damage caused by oxidation and alkylation. We hypothesized that polymorphisms in the APE1 gene are associated with risk for cervical cancer. And using Meta analysis to test this hypothesis.Methods: In a hospital-based matched case-control study, a total of 306 histologically confirmed cervical cancer cases and 306 cancer-free controls were genotyped for the -656T>G polymorphism and 1349T>G in the APE1 gene by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Electrophoretic mobility shift assay (EMSA) and luciferase expression were used to determine the binding ability of transcriptional factors to the APE1 promoter and the transcriptional activity. Published data regarding the association between APE1 1349T>G polymorphism and cancer risk showed inconclusive results. To derive a more precise estimation of the relationship, we performed a meta-analysis. Results: No association was observed for the 1349T>G polymorphism in APE1 genes. Logistic regression analysis showed that individuals with the -656TG/GG genotypes had a reduced risk for cervical cancer, compared with the -656TT genotype (OR=0.66; 95%CI=0.44-0.99). Further stratified analyses revealed that the decreased risk was more evident in younger subjects (<45 years), women with early age at menarche (≤15 years), women with early age at first intercourse (<23 years), women with early age at first live birth (<23 years), and women with more parities. EMSA indicated that the -656G allele had a higher binding affinity than the -656T allele. The luciferase assays in various cell lines further showed an increased transcriptional activity of the -656G allele compare with the -656T allele. In meta-analysis, the results showed modest associations between the APE1 1349T>G polymorphism and cancer risk (OR = 1.09, 95% CI = 1.01-1.18 for TG vs. TT; OR = 1.08, 95% CI = 1.00-1.18 for GG/TG vs. TT). In the stratified analysis, there were significantly increased risks of colorectal cancer (OR = 1.22, 95% CI = 1.03-1.43, Pheterogeneity = 0.673 for TG vs. TT; OR = 1.23, 95% CI = 1.05-1.43, Pheterogeneity = 0.909 for GG/TG vs. TT).Conclusions: The -656T>G polymorphism in the APE1 promoter region may contribute to the susceptibility to cervical cancer in Chinese populations. Further validation of the functionality of the APE1 polymorphisms and their association with risk of cervical cancer and other cancers in other ethnic populations is warranted.