Polymorphisms Of Base Excision Repair Gene And Sensitivity To Platinum-based Chemotherapy In Advanced Non-small Cell Lung Cancer

【Objective】Genetic polymorphisms involved in base excision repair are suspected to influence patient response to cancer treatment. To evaluate the effect of genetic variations on chemotherapy, we genotyped four single nucleotide polymorphisms (SNPs)in XRCC1 G28152A(Arg399Gln),XRCC1 C26304T (Arg194Trp),PARP1 T2444C (Val762Ala)及APE1 T1349G (Asp148Glu), and examined their associations with platinum-based chemotherapy response among patients with advanced non-small cell lung cancer(NSCLC).【Methods】1. Collecting the peripheral blood of advanced non-small cell lung cancer patients and following up the clinical information.2. Patient responses to treatment were determined after two cycles by the WHO criteria, which classify the response into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). For data analysis, CR and PR were combined as responders, and SD and PD were grouped as non-responders.3. Genomic DNA was isolated from the peripheral lymphocytes by proteinase K digestion and phenol/chloroform extraction, followed by ethanol precipitation. 4. Polymorphisms of XRCC1 G28152A(Arg399Gln; rs25487) , XRCC1C26304T (Arg194Trp; rs1799782) , PARP1 T2444C (Val762Ala; rs1136410) and APE1 T1349G( Asp148Glu; rs1130409)of the patients were genotyped using the TaqMan method.5. The significance of differences in frequencies and genotypes between good and poor responders was calculated using theχ~2 test. Fisher's exact test was used when the theoretical frequency had an expected count less than 1. The logistic regression model was used to calculate the odds ratios (OR) and their 95% CI. The Hardy-Weinberg Equilibrium was tested to compare the observed and expected genotype frequencies among NSCLC patients.【Results】1. Genotype frequencies are in agreement with those expected according to the Hardy-Weinberg equilibrium model(P>0.05).2. There was no significant difference in response rates according to any clinical characteristic(P>0.05).3. It was found that the XRCC1 G28152A polymorphism was significantly corre- lated with clinical benefit . When the number of XRCC1 28152A (mutant allel) increases, the response rate is elevated gradually(GG:23.4%,GA: 47.2%, AA: 61.5%) . Individuals harboring heterozygous (GA) allele in XRCC1 G28152A have a significantly higher response rate of 47.2% compared with 23.4% in wild homozygous(GG) patients (adjusted OR= 2.85,95%CI:1.291-6.277, P=0.010);The efficacy of chemotherapy of XRCC1 28152AA genotype carriers is 3.67 times that of patients carrying GG genotype (adjusted OR=3.67, 95%CI =0.779-17.362);Patients carrying at least one XRCC1 28152A allele had better clinical response than patients with wildtype allele (adjusted OR=2.48, 95%CI : 1.330 - 6.075, P=0.007) . 4. For the polymorphism of XRCC1 C26304T, homozygotes for the mutant allele (TT) had a roughly 64% decreased efficiency compared with the other patients,but the difference did not reach statistical significance(adjusted OR= 0.36,95%CI:0.040-3.298). A similar result was found in PARP1 T2444C,the response rate of chemotherapy of the patients with CC genotype signifycantly decreased compared with those with other genotypes (adjusted OR=0.37, 95%CI: 0.118-1.170).5. No significant association was found between APE1 T1349G polymorphism with clinical response[ (GG)+(TG) ]VS(TT)=1.021 (0.468-2.228).【Conclusion】The XRCC1 G28152A polymorphism of BER is significantly associated with the clinical benefit of NSCLC patients receiving platinum-based chemotherapy, patients carrying XRCC1 28152A allele had better clinical response , and the XRCC1 G28152A genotypes detected by TaqMan method may be useful in clinical applications to predict the sensitivity to chemotherapy in NSCLC patients.