Relationship Between Drug Resistance - Associated Gene Polymorphism And Platinum - Type Drug Resistance In Ovarian Cancer And Its Clinical Prognosis

CHAPTER Ⅰ Genetic polymorphism of drug-resistance for prediction of treatment outcomes in ovarian cancerDrug resistance is the main factor of poor prognosis of ovarian cancer. The essential reason of which is changes in gene function. Studies have confirmed that the resistance related single nucleotide polymorphisms (SNPs) is connected with prognosis and sensitivity of ovarian cancer chemotherapy. Therefore find out the results of predicting ovarian cancer chemotherapy molecular markers is of great significance in the treatment of ovarian cancer.This paper reviews the most comprehensive ERCCI and ABCBI and also CYP family genes based on 16 platinum and paclitaxel resistant genes of 30 SNP loci with predictive value.However, the research conclusion is not unified. So, to inspect index adjust measures to local conditions, a unified patient inclusion criteria may be a feasible scheme.Chapter Ⅱ DNA repair gene XRCC1 Arg399Gln polymorphisms and ovarian cancer susceptibility —a meta-analysisObjective:In the process of single-stranded DNA damage, the important functional protein, Arg399GIn (with the same name of gene coding of XRCC1) as the non-synonymous mutation of XRCC1 gene will cause changes in the amino acid sequence which affects the function of the protein and DNA repair capacity, and may affect the relationship with other DNA repair protein interactions that may led to an increased cancer risk. At the same time, the Arg399Gln polymorphism and the relationship between other tumor susceptibility are reported more and more frequently, such as lung cancer, pancreatic cancer, glioma. This research uses the Meta analysis to explore the susceptibility of XRCC1 Arg399Gln and sensibility of ovarian cancer.Methods:In order to analyze the OR value, have heterogeneity inspection and publish bias statistics analysis, the author uses Medline, EMBase, Cochrance, Ovid. Chinese database:China hownet, a database of ten thousand, VIP database related literature,and RevMan 5.3 as methods.As the heterogeneity is higher in Allele model (G vs A), recessive gene model (AA vs. GG+GA) and GG vs AA of codominant genetic model, the radom effect model is adopted. While, the heterogeneity is lower in Codominant model GG vs G A and super dominant genetic model (GA+AA), the fixed effects model is adopted. In a codominant base model(GG vs AA), no association with ovarian cancer susceptibility (OR= 1.31,95% CI= 0.62 2.78, p= 0.47) has been found. While in Five genetic model, no association that is related to ovarian cancer susceptibility can be found.Conclusion:there is a lack of sufficient evidence to prove that the polymorphisms of XRCC1 and Arg399Gln is associated with ovarian cancer susceptibility.Chapter Ⅲ Based on genome-wide SNP chip screening of ovarian cancer multi-resistant related functional SNPS of clinical test and verifyObjective:The SNP locus, which show the difference between the ovarian cancer patients of drug-sensitive group and drug-resistant group can be found by the detection to Human OmniZhongHua-8SNP. Analyzing the genotype and the caparison between the distribution frequency and chip datas in its clinical features, the SNP locus with predictive functions and chemosensitivity of ovarian cander may be found out.Methods:in this research,50 cases of sensitive group and 50 cases of drug-resistant group of whole genome DNA of ovarian cancer tissue will be extracted with the simple PCR method to directly amplify gene segments with correlated locus. Also, all samples of genotype will be obtained by high through-put sequencing. Then, the distribution frequency of genotype will be analyzed, the caparison between the different genotype, relationship between chemosensitivity and drug-resistance, and the relationship between risk of relapse and death and prognosis will be done.Results:9 SNP locus that may have clinical significance are found. A genotype of GRM7 rs9877193 is the dangerous factor of drug-resistance. The drug-resistance possibility of the patients with AA genotype is about 10 times to the patients with GG genotype. The difference is obvious:the meso-position PFS of GG,AG,AA genotype are 30、16、29 months, respectively. The median OS of them are 57,32 and 40 months, respectivel. Comparing two differences, no statistical significance has been found. POU6F2 rs7786697 of CC genotype is a risky factor for resistance, the possibility of CC patients of platinum resistance is about 11 times to TT type patients with a significant difference. TT, TC, CC genotype carriers median PFS 38,24,8 months respectively with a significant difference. MIR5684 rs 16999500 AA genotype may be a risky factor for resistance, but there was no statistically significant difference or not. Significantly, the risk of recurrence in patients with different genotypes has no statistically significant difference; Different genotypes in patients with no statistically significant risk of death. Median PFS of GG, GA,AA genotype carriers are 30,40,22 months, respectively. Comparing two differences, there is no statistical significance. ZNF582 rs8101140 GG type may be a risky factor, compared with TT type, the possibility of GG type resistance is 9 times to TT type with a significant difference. GG type of patients with recurrence risk is a significant difference,which was found in 2.4 times to TT type. Median PFS of genotype patients and GG genotype patients are 34 months, and 9 months respectively with a significant difference. T genotype patients and GG genotype in patients with an OS are respectively 57 and 24 months with a significant difference. CETN2 rs2301188 CC genotype may be a protective factors. The possibility of drug resistance in patients with CC type is 0.1 times of AA type with a significant difference; C genotype in patients with recurrent ovarian cancer risk is 0.48 times that of AA genotype with a significant difference; C genotype in patients with ovarian cancer mortality risk was 0.41 times that of AA genotype with a significant difference; Median PFS of AA, AC and CC genotype are 22,35,63 months, respectively. The overall comparison difference was statistically significant; C genotype carriers have a longer OS compared to patients with AA genotype. And the difference is obvious. NSDHL rs3788741 CC genotype may be a protective factors. The possibility of drug-resistance of CC genotype patients is 0.12 times of TT genotype patients with a significant difference. The death risk of the patients who carries C gene is 0.48 times of the patients with TT gene. And the significance is obvious. The median position PFS of the patients with TT genes and C genes are 18 months,7months and 38 months, respectively. There is no statistical significance of the difference. Comparing to the TT genotype patients, C genotype patients have a longer OS. The difference is of a statistical significance.Conclusions:Among nine different loci, VPS13A rs7034531, MSI2 rs4793853, LIPG rs9958734, ZNF582 rs8101140 and CETN2 rs2301188have more clinical significance. The loci may have prognosis functionsand predication functions of ovarian cancer chemotherapy sensitivity. What’s more, GRM7 rs9877193, POU6F2 rs7786697, NSDHL rs3788741 may be associated with ovarian cancer chemotherapy sensitivity. And, little clinical significance can be found in MIR5684 rs 16999500. Where as, need further verification.