| Objective: Cytochrome P450 are phase I enzymes in estrogen metabolism, whose product catechol estrogen can induce cancer, and the phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. GSTs make the specific estrogen metabolites, namely, catechol estrogen-quinones to nontoxic products. Some studies indicated that the mutation of gene coding for CYP450, the deletion of gene GSTs can lead to polymorphism resulting in the difference of enzymes activity. So these genes are correlated with the susceptibility to estrogen-dependent disorders. This study was designed to investigate the correlation of single nucleotide polymorphisms (SNPs), CYP1A1 Ile→Val, the deletions of the GSTM1 and GSTT1 gene to susceptibility of endometrial cancer in a population of Chinese North.Methods: The population-based case-control study included 171 endometrial cancer patients and 201 healthy controls. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of CYP1A1 gene were analyzed by PCR- restriction fragment length polymorphism (RFLP) analysis. Deletion polymorphisms of GSTT1 and GSTM1 gene were analyzed by Multiplex differential PCR (MD-PCR) analysis.Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant for all statistical analyses. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in the control group using Chi-square test. Comparison of the CYP1A1, GSTT1 and GSTM1 genotypes and allelotypes distributions in cancer patients and healthy controls were performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model.Results:1 The comparison of the value of menarche age and menopause in case with control groupsTwo groups of menarche age<15 and menarche age≥15 were divided into case and control groups, the percentage was 32.2% and 67.8% in case, 43.4% and 56.7% in control. The percentage of menarche age≥15 in case was obviously greater than that in control. By statistical analysis, there was significant difference between menarche age≥15 and menarche age<15 in two groups (χ2=4.813, P=0.028, OR=1.610, 95%CI=1.052~2.463). Two groups of premenopause and post-menopause were divided into case and control groups, the percentage were 32.2% and 67.8% in case, 36.8% and 63.2% in control. The difference was not significant in two groups (P>0.05).2 The comparison of CYP1A1 Ile→Val polymorphism in case with control groupThe distributions of CYP1A1 Ile→Val genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (P>0.05). The frequency of wild genotype (Ile/Ile), heterozygous genotype (Ile/Val), and homozygous genotype (Val/Val) were 59.1%, 37.4%, 3.5% in case, and 59.7%, 36.3%, 4.0% in control. The frequency of heterozygous genotype and homozygous genotype in case were not obviously different from those in control (P>0.05). The allele frequency of A and G were 77.8%, 32.2% in case, 77.9% and 32.1% in control. No significant difference was shown between the alleles of two groups (P>0.05). Contrast with wild genotype (Ile/Ile), merging heterozygous genotype (Ile/Val) into homozygous genotype (Val/Val), the difference between the case and control groups was not significant (P>0.05). When stratified for the menarche age and menopause, no significant difference in genotype and allele distributions was found between patients and control groups in CYP1A1 Ile→Val (P >0.05). 3 The comparison of GSTM1 and GSTT1 polymorphisms in case with control group3.1 The frequency of GSTM1nonull (GSTM1+) and GSTM1null (GSTM1-) genotypes were 36.3%,63.7% in case , 43.3%,56.7% in control. The gene deletion rate in case was higher than that in control, but no statistical significance (P>0.05). The frequency of GSTT1+ and GSTT1- genotypes were 59.1%,40.9% in case,45.8%,54.2% in control, the gene deletion rate in case was lower than that in control and the difference was significant. (χ2=6.5, P=0.011, OR=1.709, 95%CI=1.132~2.582). 3.2 According to whether or not menopause, the polymorphisms of GSTM1 were not different between the case and control group (P>0.05), same as GSTT1 polymorphisms in premenopause (P>0.05). But in post-menopause, the frequency of GSTT1+ and GSTT1- genotypes were 58.6%,41.4% in case, and 42.5%,57.5% in control. The percentage of GSTT1- in case was obviously lower than that in case and the difference was significant (χ2=6.231, P=0.013, OR=0.522, 95%CI=0.313 ~0.870).3.3 According to menarche age, there was no significant difference about GSTM1 polymorphisms between the case and control group (P>0.05). The frequency of GSTT1+ and GSTT1- genotypes were 69.1%,30.9% in case, and 47.1%,52.9% in control, in the group of menarche age<15. The percentage of GSTT1+ in case was obviously greater than that in control. The difference was significant between the case and control group (χ2=6.440, P=0.011, OR=0.399, 95%CI=0.196~0.811). In the group of menarche age≥15, there was no significant difference about GSTT1 polymorphisms between the case and control group (P>0.05).3.4 The associated analysis of GSTT1, GSTM1 polymorphisms and the risk of the endometrial cancerIt was reported that the GSTM1+ was the function pattern, and the gene deletion rate of GSTT1 was high in Chinese people. So the pattern of GSTM1+ and GSTT1- was regarded as the non-exposed factor, the pattern of GSTM1- and GSTT1+ as the exposed factor, in our statistical analysis. Using Chi-square test, there was a significant difference between the case and control group (χ2=9.82, P=0.02). And compared to the GSTM1- and GSTT1+ genotype, the odds ratio with other groups as GSTM1- and GSTT1- group, GSTM1+ and GSTT1+ group, GSTM1- and GSTT1+ group were 1.797(0.962~3.356), 2.402(1.230~4.690) and 2.455(1.333~4.521) respectively.4 The relationship between the unification among mutation of CYP1A1, GSTM1, GSTT1 and the risk of the endometrial cancer. We analyzed the unification among genes of CYP1A1, GSTM1 and GSTT1 by means of two-sided contingency tables using Chi-square test.The percentage of CYP1A1 mutation genotype (including heterozygous genotype and homozygous genotype) with other GSTM1 and GSTT1 genotypes in case was significantly higher than that in control, when was compared to the wild genotype of CYP1A1 with the GSTM1+ and GSTT1- genotype (χ2=4.93, P=0.026, OR=2.123, 95%CI=1.093~4.127). This indicated these genes had a synergistic effect on the risk of endometrial cancer.Conclusions:1 The menarche age correlated with the risk of endometrial cancer. The individual with menarche age≥15 has a high risk to get endometrial cancer (OR=1.610). This indicated older menarche age is one of the predisposing factors in endometrial cancer.2 The CYP1A1 Ile→Val polymorphism has no association with the risk of endometrial cancer. According to menarche age and menopause age, there were no relationships with the endometrial cancer as well.3 The GSTM1 polymorphism has no association with the risk of endometrial cancer. According to menarche age and menopause age, there were no relationships with the endometrial cancer as well.4 The GSTT1 nonnull genotype can increase the risk of endometrial cancer. When post-menopause or menarche age is early, the individual with GSTT1 nonnull genotype is susceptible to the endometrial cancer.5 According to the associated analysis, the GSTT1 nonnull genotype has a stronger association with endometrial cancer than the GSTM1 null genotype, and there was a synergistic effect between two factors in the occurrence of endometrial cancer.6 There was unification in genetic polymorphism of CYP1A1, GSTM1 and GSTT1 in the risk of endometrial cancer.
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