| Background and objective: AXIN2 is a tumor repressor involved in thenegatively regulation of Wnt/β-catenin pathway, implicated in cancer progression and development. The correlation between a functional single nucleotide polymorphism(SNP) in AXIN2 exon 1, rs2240308 and cancer risk has been examined in several case-control studies, whereas the conclusions were inconsistent. Here we performed a meta-analysis to estimate the role of rs2240308 in cancer risk. A total of 8 studies were included in this meta-analysis(1503 controls and1559 cancer cases). The pooled odds ratios(OR) with the 95% confidence intervals(CI) were assessed to estimate the association of the AXIN2 polymorphism rs2240308 and a susceptibility to cancer. A significantly decreased overall cancer risk was observed in the heterozygous(CT vs. CC),homozygous(TT vs. CC), allelic(T vs. C) and dominant(CT+TT vs. CC) models(P<0.005), rather than in the recessive(TT vs. CT+CC) model(P=0.092). AXIN2 rs2240308 polymorphism was also associated with decreased lung cancer risk under all five models. However, the AXIN2 polymorphism rs2240308 wasn’t associated with cancer risk under any above models in Turkish population, and under homozygous(TT vs. CC), heterozygous(CT vs. CC), recessive(TT vs. CT+CC) models in Japanese population. These findings implicate that AXIN2 polymorphism rs2240308 race-specifically and significantly correlates with decreased cancer risk.Methods: The literature searches were performed by searching Pub Med, EMBASE and MEDLINE(updated to February, 2015). Thecombination of search terms includes “AXIN2 or axin 2”, and “polymorphism or variant or SNP”, and “cancer or tumor or carcinoma”. The accuracy of the extracted data was validated by two researchers. Both researchers obtained the same conclusion. The collected datas included the publication year,first author, cancer type,population, cancer type, the numbers of cases and controls, matching criteria,genotype distributions, matching criteria, genotyping methods, control source and HWE.We performed the meta-analysis with Stata Statistical package 12.0(Stata Corp LP, College Station, TX), and used the heterozygous(CT vs. CC),homozygous(TT vs. CC),recessive(TT vs. CT+CC), dominant(CT+TT vs. CC) and allelic(T vs. C) models in this meta-analysis. The association between the AXIN2 polymorphism rs2240308 and cancerrisk was confirmed by the OR and their corresponding 95% CI. The Z test was used to estimate the statistical significance of the pooled OR value, and then P<0.05 was considered statistically significant differences. Heterogeneity test was evaluated by the Chi-squared test and I-squared test, P<0.05 for Chi-squared test was considered that heterogeneity exist among the studies, the OR were determined with the random-effects model when P<0.05, whereas P>0.05 for Chi-squared test represented that the fixed-effects model was application. The sensitivity was assessed for assessing the stability of the results. Publication bias was assessed by the use of Egger’s test andfunnel plot.Results: Totally 169 papers were obtained with the combination of search terms as “AXIN2 or axin 2”, “polymorphism or variant or SNP”, and “cancer or tumor or carcinoma”. 143 references were excluded by reading the title and abstract. After scanning the full text, 8 articles were included in this meta-analysis. 1559 cancer cases and 1503 controls were included in these articles. The 1559 cancer cases included lung cancer, colorectal cancer, head and neck cancer, astrocytoma, prostate cancer and ovarian cancer. The populations included in these studies were Chinese, Japanese, Turkish, Iranian and Polish. All the included studies were consistent with the inclusion and exclusion criteria as indicated in detail in Methods. The genotype in control populations was conformed to Hardy–Weinberg equilibrium(HWE). The heterogeneity among the selected studies was evaluated by Chi-squared test, P value <0.05 means the heterogeneity was observed. If the heterogeneity among the selected studies was observed, the random-effects model would be applied to analysis the odds ratios(ORs) and their respective 95% confidence intervals(CIs); otherwise the fixed-effects model was used. Since the heterogeneity was not observed in homozygous(TT vs. CC), heterozygous(CT vs. CC), dominant(CT+TT vs. CC), allelic(T vs. C) and recessive(TT vs. CT+CC) models(all P values >0.05, the fixed-effects model was used in the analysis. The ORs and their respective 95% CIs were used to evaluate the association between AXIN2 polymorphism rs2240308 and cancer risk. The Z test was applied to test the statistical significance of the pooled OR value. A significantly decreased overall cancer risk was found in the homozygous(TT vs. CC:OR=0.72, 95% CI: 0.58-0.89, P=0.003), heterozygous(CT vs. CC: OR=0.74, 95% CI: 0.63-0.86, P<0.001), dominant(CT+TT vs. CC: OR=0.73, 95% CI: 0.63-0.84, P<0.001) and allelic(T vs. C: OR=0.82, 95% CI: 0.74-0.90, P<0.001) models, but the decreased overall cancer risk was not observed in the recessive(TT vs. CT+CC: OR=0.84, 95% CI: 0.69-1.03, P=0.092) model.The fixed-effects model was used in the analysis of lung cancer subgroup due to the absence of heterogeneity in all above models. Consistently, AXIN2 rs2240308 was significantly associated with decreased lung cancer risk in these models, i.e., the homozygous(TT vs. CC: OR = 0.52, 95% CI: 0.36-0.74, P< 0.001), heterozygous(CT vs. CC: OR = 0.73, 95% CI: 0.59-0.91, P=0.005), dominant(CT+TT vs. CC: OR=0.69, 95% CI: 0.56-0.85, P<0.001), recessive(TT vs. CT+CC: OR=0.61, 95% CI: 0.43-0.85, P=0.003) and allelic(T vs. C: OR = 0.73, 95% CI:0.63-0.85, P< 0.001) models.Subgroup analysis based on population was also performed in this analysis. Heterogeneity was not observed in all five models and thus the fixed-effects model was employed in this meta-analysis. The association between AXIN2 polymorphism rs2240308 and cancer risk was not observed in Turkish population under all these models, including the homozygous(TT vs. CC: OR=0.75, 95% CI: 0.46-1.22, P=0.250), heterozygous(CT vs. CC: OR=0.72, 95% CI: 0.50-1.03, P=0.069), dominant(CT+TT vs. CC: OR=0.73, 95% CI: 0.52-1.02, P=0.064), recessive(TT vs. CT+CC: OR=0.91, 95% CI: 0.58-1.42, P=0.669) and allelic(T vs. C: OR=0.83, 95% CI: 0.66-1.05, P=0.130) models. However, the AXIN2 polymorphism rs2240308 was significantly associated with decreased cancer risk in Japanese under the dominant(CT+TT vs. CC: OR=0.71, 95% CI: 0.52-1.97, P=0.032) and allelic(T vs. C: OR=0.77, 95% CI: 0.61-0.97, P=0.024) models, but not in the homozygous(TT vs. CC: OR=0.61, 95% CI: 0.36-1.01, P=0.056), heterozygous(CT vs. CC: OR=0.74, 95% CI: 0.53-1.03, P=0.075) and recessive(TT vs. CT+CC: OR=0.71, 95% CI: 0.44-1.15, P=0.164) models.Conclusions: These findings indicate that AXIN2 polymorphism rs2240308 significantly and race-specifically correlates with decreased cancer risk. |
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