Relationship Between Regulome-SNPs(PARP1 Rs17573756 And XRCC3 Rs7142555)and NSCLC Patients Respond To Platinum Chemotherapy

Background:Lung cancer is the most common malignant tumor and leading cause of cancer-related death worldwide.Although the treatment of lung cancer has achieved certain results,the incidence and mortality rate of lung cancer are still increase in China,which seriously endanger people’s life and health.Platinum-based chemotherapy is the first choice for advanced NSCLC,but not all patients benefit from it,there are great individual differences in efficacy.Studies have shown that genotyping can help us predict the prognosis and risk of lung cancer patients.It has also been shown that PARP1 and XRCC3 play an important role in DNA damage caused by platinum drugs.However,it is not clear whether there has a correlation between SNPs(PARP1 rs17573756 and XRCC3 rs7142555)and the efficacy of platinum drugs in NSCLC patients.Objective:In this study we aimed to explore the correlation between the efficacy of platinum drugs and SNPs(PARP1 rs17573756 and XRCC3 rs7142555),and providing a theoretical basis for the clinical prediction of platinum drugs therapy in the treatment of NSCLC efficacy markers.Materials and methods:1.Blood samples were collected from 505 patients with non-small cell lung cancer who received platinum drugs therapy in the Hospital of Yanbian University and Yanbian Cancer Hospital and Hospital of Deagu Uniwesity from 2008 to 2016.2.Regulome-DB database were used to selection SNPs that may be related to lung cancer.3.NCBI-SNP and HapMap-SNP databases were used to selection the minor allele frequency(MAF)of less than 10%SNPs and those linkage disequlibrium(LD)r2>0.8 SNPs.4.DNA in whole blood was extracted with whole blood DNA extraction kit(Kurabo Company,South Korea).5.Entrusted Beijing BGI Company to conduct the second-generation sequencing of the proposed DNA.6.PARP1 rs17573756(G>C)and XRCC3 rs7142555(G>T)were genotyped by PCR-RFLP technique,and the accuracy of the second generation sequencing was detected.7.t-test and χ2 test were used to detect whether the differences in age,gender,smoking state,histology and stage between the invalid group and the effective group were statistically significant.8.The distribution frequency of PARP1 rsl7573756 and XRCC3 rs7142555 genotypes in the invalid group and the effective group was analyzed by χ2 test.9.Logistic regression analyses was used to analyze the correlation between SNPs(PARP1 rs17573756 and XRCC3 rs7142555)and the efficacy of platinum drugs in NSCLC patients.10.Combining the genotypes associated with chemotherapy efficacy and studying the combined effect of their SNPs.11.SPSS 26.0 was used for statistical processing of the all data.Results:1.The genotypes of PARP1 rs17573756 and XRCC3 rs7142555 met Hardy-Weinberg genetic balance test.2.PARP1XRCC3 rs1 7573756 has three genotypes:GG,GC,CC;rs7142555 has three genotypes:GG,GT and TT.3.t-test andχ2 test results showed there were also no significant differences between two groups in terms of age,sex,smoking,histology(P>0.05).4.χ2test results showed that the genotype distribution frequency of PARP1 rs17573756 and XRCC3 rs7142555 had significant difference between invalid and effective patients.5.Logistic regression analyses showed that in PARP1 rs17573756,patients who with CC genotype had poor response to chemotheraphy than those with GG wild type patients(Adjusted OR=4.894,95%CI=1.404-17.062,P=0.013).The risk of CC genotype was significantly higher than that of GG and GC in recessive models(CCvs.CG/GG:Adjusted OR=4.85,95%CI=1.385～16.668,P=0.013).In XRCC3 rs7142555,patients who with GG genotype had poor response to chemotheraphy than those with TT genotype patients(Adjusted OR=0.542,95%CI=0.448-0.957,P=0.037).In the dominant model,the risk of GG genotype was significantly higher than that of GT and TT combined genotype(GGvs.GT/TT:Adjusted OR=1.593,95%CI=1.117～2.273,P=0.010).6.χ2 test results showed that combined genotypes distributions were significantly different between invalid and effective patients(P=0.003).And risk genotype number are inversely correlated with chemotherapy response,compared with those with 0 risk genotype,subjects carrying 1-2 risk genotypes had worse respond to chemotherapy(Adjusted OR=1.664,95%CI=1.162-2.383,P=0.005;Adjusted OR=4.867,95%CI=1.026-23.094,P=0.046,respectively).Conclusion:PARP1 gene rs17573756(G>C)and XRCC3 gene rs7142555(G>T)polymorphisms were associated with the efficacy of platinum drugs therapy for NSCLC.NSCLC patients with PARP1 gene rs17573756 CC and XRCC3 gene rs7142555 GG had poor outcomes.