| Objective: Ovarian malignancy is one of the most common gynecological malignancy and 90% is Epithelial ovarian cancer (EOC). The management of ovarian cancer involves surgery in order to achieve tumour cytoreduction followed bychemotherapy.Currently,combination chemotherapy is clinically used to treat EOC, but drug resistance is a major obstacle to the successful treatment of EOC patients. Therefore, overcoming resistance to chemotherapy was a major goal of cancer research that could dramatically improve clinical outcomes for patients with EOC. Several research shows that multidrug resistance gene is highly expression in cancer cells and could contribute to multidrug resistance , which is the reason of chemotherapy failed. Mutational analyses have revealed that the MDR1 gene is highly polymorphic and it is extensively used to investigate chemotherapy sensitivity relationships. The aim of our work was to assess the association between frequency of genotype distribution of C3435T, G2677T/A and C1236T polymorphisms and chemotherapy sensitivity in EOC patients. We hope to offer some evidences for the treatment of ovarian cancer at molecular biology level.Methods: 130 epithelial ovarian cancer patients were included in the study and were routinely treated with optimal cytoreductive surgery followed by platinum or carboplatin based chemotherapy. Five ml of venous blood from each subject was drawn in vacutainer tubes. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. MDR1 C3435T, C1236T and G2677T/A SNPs were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis.Statistical analysis was performed using SPSS11.5 software package (SPSS Company, Chicago, Illinois, USA). Hardy-Weinberg analysis was performed to compare the three genotype frequencies using the Chi-square test. The test was used to examine the difference of ages between drug-sensitivity group and drug-insensitivity group. Univariate comparisons of allele and genotype distribution were performed using Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model. The MDR1 C3435T, C1236T and G2677T/A haplotype frequencies and linkage disequilibrium coefficient were estimated by using EH linkage software and 2ld software. P<0.05 was considered significant for all statistical analyses.Results:1 The MDR1 C3435T, C1236T and G2677T/A genotypes were compatible with those expected from Hardy-Weinberg equilibrium (r2=0.07, r2=1.00 or r2=2.75).2 There were no significant differences in genotype and allele frequencies distributions of the MDR1 C3435T polymorphism between drug-sensitivity groups and drug-insensitivity groups (P=0.842 and 0.687, respectively). Compared to the C/T+T/T genotypes, the C/C genotype had no association with the drug-sensitivity for epithelial ovarian cancer (OR=1.21, 95%CI=0.48～3.09). Stratification analysis showed no significant difference between the drug-sensitivity groups and drug-insensitivity groups in allele or genotype distributions of MDR1 C3435T according to the pathological type, clinical stage and patient age of epithelial ovarian cancer stratify (P>0.05)3 There were no significant differences in genotype and allele frequencies distributions of the MDR1 C1236T polymorphism between drug-sensitivity groups and drug-insensitivity groups (P=0.744 and 0.687, respectively). Compared to the C/T+ C/C genotypes, the T/T genotype had no association with the drug-sensitivity for epithelial ovarian cancer (OR=0.851, 95%CI=0.42～1.74). Stratification analysis showed no significant difference between the drug-sensitivity groups and drug-insensitivity groups in allele or genotype distributions of MDR1 C1236T according to the pathological type, clinical stage and patient age of epithelial ovarian cancer stratify (P>0.05). 4 MDR1 G2677T/A genotype and allele frequencies did not differ between drug-sensitivity groups and drug-insensitivity groups (P=0.987 and P=0.589 respectively). Compared to the G/T+T/T+T/A genotypes, the G/G genotype did not significantly modify the drug-sensitivity for epithelial ovarian cancer with odds ratio of 1.01(95%CI=0.42～2.40). When stratified by pathological types, the frequencies of the G allele of the mucinous ovarian cancer were significantly higher in drug-sensitivity groups(60.0 %)than those in drug-insensitivity groups (18.8%), there was statistical difference between the two groups(P=0.046). Individuals with the G allelotype(G/G + G/T genotype)significantly had a relation on the increased drug-sensitivity of the mucinous ovarian cancer (OR=0.15,95%CI=0.03～0.91).5 The combined effect of MDR1 C3435T, C1236T and G2677T/A SNPs was analyzed by EH and 2ld software. The result showed that the C3435–T1236–T2677 and T 3435–T 1236–G2677 haplotype was the most common, which was 61.92%. But the frequencies of four haplotypes (C3435–T1236–T2677,T3435–T1236–G2677,T3435–C1236–A2677,T3435–C1236–G2677) of MDR1 C3435T, C1236T and G2677T/A were not significantly different between the drug-sensitivity groups and drug-insensitivity groups (P>0.05). In addition, C3435T and C1236T were in complete linkage disequilibrium (D'=1.000, P =0.282), C3435T and G2677T/A were in strong linkage disequilibrium (D'=0.906, P=0.479) , C1236T and G2677T/A were in moderate linkage disequilibrium (D'=0.644, P=0.203).6 According to the chemotherapy of epithelial ovarian cancer stratify , stratification analysis showed no significant difference between the drug-sensitivity groups and drug-insensitivity groups in genotype distributions of MDR1 C3435T, C1236T and G2677T/A (P>0.05).Conclusions:1 The MDR1 C3435T, C1236T SNP may have no association with chemotherapy sensitivity on epithelial ovarian cancer in north Chinese population.2 Individuals with the G allelotype (MDR1 G2677T/A G/G+G/T genotype) significantly had a relation on the increased drug-sensitivity of the mucinous ovarian cancer.3 Although the MDR1 C3435T, C1236T and G2677T/A SNPs showed linkage disequilibrium in the women of North China, there were no association between the haplotype of MDR1 C3435T, C1236T and G2677T/A polymorphisms and the chemotherapy sensitivity on epithelial ovarian cancer. |
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