The Relevance Between Single Nucleotide Polymorphisms Of XRCC1 And Radiation Effect Of Patients With Advanced NSCLC

Background:Non-small cell lunng cancer(NSCLC) is one of the most serious threats to human health,it accounts for 80-85 percents of all lung cancer,and it falls into the same category of turmor with medium sensitive to radiotherapy. But the curative effect of radiotherapy with NSCLC patients is frequently less than satisfactory,so increasing sensitivity and improving security turned into the hot clinical problems to be solved.In our clinical work,the same tumor tissue has different response to radiotherapy,reachers show that this difference is related to the mechanism of repair of DNA damage.On the other hand, response rate improved and survival time longer accompanied with the increased dose of radiation,accordingly,it can increase the rate of radiotherapyinduced skin,pulmonary and esophagus injury in NSCLC patients. Clinical manifestations of these damages are various.It is lack of measures of the predictive,and the trend of injure can not be reverse.Therefore,the precaution is more important than therapeutic method.Radioactive rays primarily cause a damage to DNA by single strand break(SSB), double strand breaks(DSB), DNA base damage, DNA crosslink and DNA-protein crosslinks.The DSB is the most serious injury of all,but DNA base damage and SSB are the most,and base-excision repair(BER) is the main recovery mechanism to above-mentioned DNA damage.Probably,this mechanism not only decides the radiosensitivity but also affects the severity of radiation damage.Recent studies have shown that X-ray repair cross complementing gene 1-9(XRCC1-XRCC9) is the indispensable parts of process of repair DNA damage after radiation injury.XRCC1 is an important constituent of DNA base-excision repair/single strand break repair,it is the first gene which can influence the ionization sensitivity of mammal cells.The proteins encoded by it play important positions on the field of base excision repair and DNA single-strand break repair as a scaffolding protein that may connect DNA polymerase β,DNA ligase Ⅲ and poly(ADP-ribose) polymerase(PARP),suggesting XRCC1 SNP directly impact the actual capacity of repair of DNA damage.There are three locuses of single nucleotide polymorphisms involved XRCC1 coding sequence,the sites are G28152A(Arg399G1n), C26304T(Arg194Trp) and G27466A(Arg280His).Generally recognizing there are differences in race and religions about the XRCC1 allele frequency.Because the Arg399 Gln locus is located in the functional domain bonding XRCC1 protein and PARP, it is generally acknowledged that the functions of proteins are affected by the polymorphisms of it.It is reported that XRCC1 SNP is possibility connected with radiation injury of various tumours,but none regarding non-small cell lung cancer patients. This research assesses allele frequency of NSCLC patients in Asian by detecting XRCC1 SNPs, provides data for further study on the role of XRCC1 gene in physiology and pathology,and that researches the relevency between XRCC1 Codon399 SNP and radiation effect and side effect by analyzing the different therapeutic effect and radiation damage between various genotype of XRCC1 Codon399 after follow-up visiting at three and six months after radiation.Consequently,it provides clinical evidence of increasing the radiosensitivity and radiological safety, optimizing criterion of clinical assessments and treatments,to provide a new ideas that forecasting radiation injury. Materials and Methods:This study involved 60 patients with squamous carcinoma, adenocarcinoma, adenosquamous carcinoma and large cell carcinoma by percutaneous lung puncture biopsy(PNLB),neoplasm staging Ⅲ-Ⅳ stage,without radiotherapy or chemotherapy in two months.We detect the three genotypes of XRCC1 Codon399 by xTAG liquid chip before radiotherapy,follow-up visit radiation effect and acute radiation-induced injury at 3 months after radiation and late radiation-induced injury at 6 months after radiation,to explore the predictive effect of radiosensitivity and radiological safety with XRCC1 SNP. Results:The results suggest that there no significant differences between various genomes with remission rate at 3 months after radiation. The patients with Arg/Gln heterozygote had a higher rate of acute radiation-induced pulmonary injury than the others(P<0.05), meanwhile the patients with Arg/Gln heterozygote and Gln/Gln homozygote were easier to injury mucous membrane of upper gastrointestinal tract(P<0.05).There were no significant differences among the three genotypes involved cute irradiation-induced injury with skin, esophagus, leukocyte blood platelet(P > 0.05).Follow-up visiting the late radiation-induced injury at 6 months after radiation,some of patients had been used in combination with chemotherapy or targeted therapy,so the curative effect cannot be analyzed wit only one element,we made a special effort to investigate and study the late radiation-induced injury. Research findings show that the patients with Arg/Gln heterozygote had a higher rate of late radiation-induced pulmonary injury than the others(P<0.05), meanwhile the patients with Arg/Gln heterozygote and Arg/Arg homozygote were easier to injury heart(P<0.05).There were no significant differences among the three genotypes involved late irradiation-induced injury with skin and esophagus(P>0.05). Conclusion:There are a number of studies about the correlation between XRCC1 Codon399 SNP or its protein expression and the curative effect or side effect of radiotherapy in esophagus cancer, nasopharynx cancer, breast cancer, stomach cancer, the conclusions are in different. But one thing for certain,there are various radioreactions after radiotherapy with different genotypes.There is no clinical report involved the radiosensitivity and radiological safety in NSCLC patients at present.These experiment’s selection objects were NSCLC patients in Ⅲ-Ⅳ stages,and detected XRCC1 Codon399 SNP by xTAG liquid chip which was provided with higher sensibility and specificity.There was no correlation between XRCC1 Codon399 SNP and radiosensitivity in end-stage NSCLC patients with a short-term follow-up,but the genotypes affect acute radiation injury with pulmonary and digestive tract.Further follow-up discoveried that XRCC1 genotypes were related to late radiation injuries with pulmonary and cardiac.The consequence suggested that we can use XRCC1 Codon399 SNP as one of the significant predictors of irradiation-induced injuries of normal tissue to the advanced NSCLC patients after radiation.