| Objective:Genetic polymorphisms of DNA repair genes are associated with differential enzyme activity and may affect response rates after platinum-based chemotherapy for non small cell lung cancers (NSCLCs) and the survival times. This study explored the relationship between genetic polymorphisms of DNA repair gene and survival time of platinum-based regimens chemotherapy in advanced NSCLC. We genotyped patients to detect polymorphisms of DNA repair gene XRCC1 (X-ray repair cross completing group1) codon 399 and XPD (Xeroderma pigmentosum group D) codon 751 and assessed the relationship between survival time of patients who had been treated with platinum-based regimen and genetic polymorphisms of XRCC1 codon 399 and XPD codon 751.Methods:From March 1, 2005 to December 31, 2008, totally 108 advanced patients who had histologically confirmed NSCLC in Jiangsu Cancer Hospital and Research Institute were treated with platinum (cisplatin or carboplatin) based chemotherapy, and clinical response was evaluated after 2 cycles. XRCCl codon399 and XPD codon751 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods using DNA samples isolated from peripheral blood collected before treatment. Survival status of patients was obtained through follow up by telephone. The relationship between genetic polymorphisms and survival time after platinum-based chemotherapy were analyzed by STATA software.Results:(1) The genotype frequencies of XRCC1 and XPD were consistent with Hard- Weinberg equilibrium (P=0.44, P=0.28). Among 108 patients, the genotypes of XRCC1 codon 399 were Arg/Arg 5(4.6%),Arg/Gln 43(39.8%) and Gln/Gln 60 (55.6%) respectively; The genotypes of XPD codon 751 were Lys/Lys 86(81.1%) and Lys/Gln 20 (18.9%). Gln/Gln genotype was not found.(2) Among the assessed NSCLC patients, the overall response rate of chemotherapy was 21.6%. The median survival time (MST) was 29 months (95%CI, 7.0-39.0 months) in patients with XRCC1 codon 399 Arg/Arg genotype, which was higher than 21 months (95%CI,11.5-30.9 months) in Arg/Gln genotype and 15 months (95%CI,11.9-21.1 months) in Gln/Gln genotype, the difference was still not statistically significant (log-rank test, P=0.09). In the Cox proportional hazard model, after adjusting by gender, age, stage, histology, Karnofsky performance status and chemotherapy regimen, the hazard ratio(HR) for patients with XRCC1 codon 399 Arg/Arg genotype was 0.58 (95%CI, 0.17-2.04; P=0.40). In this study, the XPD codon 751 (Lys/Gln) genotypes were not associated with decreased overall survival: patients with the Lys/Gln genotype had a MST of 26.5 months (95%CI,7.7-33.8 months), those with the Lys/Lys genotype had a MST of 15.5 months (95%CI,12.4-21.0 months; log-rank test, P=0.50). In the Cox multivariable model, after adjusting for gender, age, stage, histology, Karnofsky performance status, treatment regimen, the HR for patients with XPD codon 751 Lys/Gln genotype was 0.67 (95%CI, 0.36-1.23; P=0.20).(3)The relationship between combination of XRCC1 and XPD polymorphisms and overall survival was analyzed, patients with XRCC1 Arg/Gln and XPD Lys/Gln genotype were associated with a higher response rate (33.33%) and MST (35.5 months), compared with other genotypes patients, in the Cox proportional hazard model, after adjusting by gender, age, stage, histology, Karnofsky performance status and chemotherapy regimen, the overall survival difference did not reach statistical significance (HR for patients with XRCC1 Arg/Gln and XPD Lys/Gln genotype, 049; 95%CI, 0.14-1.68; P=0.26).Conclusions:(1) In this study, the genotypes of DNA repair gene XRCC1 codon 399 were mainly distributed to Gln/Gln and Arg/Gln, Arg/Arg genotype appeared only in few cases. Lys/Lys genotype accounted for the most of the XPD codon 751.(2) Our results suggested no influence of the XRCC1 codon399 (Arg/Gln) and XPD codon751 (Lys/Gln) genetic polymorphisms on survival in advanced NSCLC patients with platinum-based chemotherapy.
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