Association Of GSTP1 And XRCC1 Gene Polymorphisms With Clinical Outcome Of Advanced Non-Small Cell Lung Cancer Patients

Part OneConnection Between Gene Polymorphism of GSTs and Chemotherapeutic Effect of Platinum Drugs for Advanced Non-small Cell Lung CancerBackground and PurposeLung cancer is the highest tumor in the morbidity and mortality in the world today, it is a major public health problem worldwide in 2012 lung cancer men new cases around the world is about 1.242 million,1.099 million deaths, about 583000 women, deaths of 491000, the world’s first malignant tumor morbidity and mortality, ranks first in the tumor incidence in men, women in the incidence of malignant tumor in the fourth Current method the treatment of non-small cell lung cancer chemotherapy radiotherapy and surgery, but because there is no obvious clinical symptoms of early lung cancer, when patients were diagnosed, only about 15% of the patients can through early findings and surgery treatment, most patients have found belong to middle-late, lost the best operation and treatment opportunity, can only accept systemic chemotherapy, so the prognosis of patients with lung cancer is poorer, chemotherapy has become the main way for the treatment of advanced lung cancer. However, current chemotherapy does not achieve good therapeutic effects and only 5%～15% patients receive obvious benefit. Now we recommend individualized therapy for NSCLS. The so-called individualized therapy is selective remedy that differs according to variation of biology of tumor and pharmacokinetics. Glutathione S Transferases (GSTs), which belongs to type Ⅱ metabolizing enzyme, is a drug-metabolizing enzyme with multiple physiological functions. It includes four families----GSTA、GSTM、GSTT、GSTP. They can promote the combination of polar compound and glutathione (Glutathione, GSH) and prevent damage of polar compound for DNA. In addition, they achieve the purpose of lowering toxic effect by combination of lipophilic cytotoxic drugs and dyes carcinogens to make them more soluble in water. And they play an important role in protecting integrity of cellular DNA and promoting repair for damaged DNA. By affecting corresponding enzyme in molecular structure, functions and expression level, the gene polymorphism of GSTs can influence detoxifying ability of cells. So it is regarded that GSTs relate to tumor susceptibility and sensibility of chemotherapeutics for patients. Nowadays, studies of polymorphism of GSTs concentrate more on the field of tumor susceptibility such as lung cancer and less on the connection of chemotherapeutics. platinum drugs main targets for the DNA molecule, give play to the role of cancer after the platinum drugs into cells, combined with double-stranded DNA within the tumor cells, Pt-DNA adduct formation, cause DNA damage, transcription and DNA replication dysfunction, leading to tumor cell death, achieve antitumor. DNA damage repair there are at least five ways:nucleotide excision repair pathways (nucleotide excision repair, NER), mismatch repair pathways (mismatche repair, MMR) base excision repair pathways (bace excision repair, BER) and fracture repair double-stranded (DNA double strand break repair, DDSBR) and non homologous end connection (nonhomologous end joining, NHEJ) as active DNA damage repair pathways, BER catalytic substrate scope extensive, BER repair dysfunction closely associated with antitumor drug resistance. XRCCl gene on chromosome 19 q13.2-13.3, XRCCl is the important component of base excision repair system BER XRCCl gene encoding area if there are amino acids can lead to change single nucleotide polymorphisms, will influence the activity of XRCCl. There are a variety of single nucleotide polymorphisms in XRCCl, one of the most common is the tenth exons, Arg399Gln (28152Arg→Gln); Ninth exons, Arg280His (27466 Arg→His); For 6 exons, Arg194Trp (26304Arg→Trp). Individuals, in patients with cancer of XRCCl gene polymorphisms can alter protein activity, influence the repair function, when the repair function, such as platinum chemotherapy drug resistance, and when the activity is reduced, DNA repair function abate, enhanced sensitivity to chemotherapy drugs. This paper pay attention to the connection between gene polymorphism of GSTs and XRCCl and chemotherapeutic effect of platinum drugs for advanced non-small cell lung cancer, especially the field of chemo-sensitivity and lifetime, etc.Materials and MethodsIn this paper, I will take 156 advanced non-small cell lung cancer patients, who were diagnosed by pathologists between July,2009 and June,2012 in our hospital and meet the eligibility, as study objectives. Using EDTA-Na2 anticoagulant tube before chemotherapy pump case group and control group subjects venous blood 5 ml, placed in-80 spare kept in a refrigerator According to the SNP loci by Sequenom company Assay Design3.1 software to design primers after extraction of genomic DNA for PCR amplification, the fluorescent signal collected by PCR instrument, according to the fluorescence signal to map the GSTM1 GSTT1 loss or exist, sequencing GSTP1 genotypes 11e105Val loci, XCRR1 Arg194Trp, Arg280His and Arg399Gln loci. For patients on the basis of cisplatin chemotherapy, according to RECIST criteria, will complete response and partial judged to be sensitive to chemotherapy group of patients in remission; Part of the stability and progress to chemotherapy is not sensitive or resistant groups In small cell lung cancer patients were followed up at once a month, all patients were followed up in July 2014, is sensitive to chemotherapy in patients with statistics and survival time, points GSTM1, GSTT1, GSTP1 11e105Val, XCRR1 Arg194Trp, Arg280His and Arg399Gln the relationship between gene polymorphism and patients survival Using SPSS 19.0 (version 19.0, SPSS Inc., Chicago, IL, USA) were analyzed.ConclusionBy Hardy-Weinberg examination to lle105Val site of GSTP1 gene, GSTP1 gene satisfies Hardy-Weinberg law (P= 0.79).Carry GSTP1 11e105Val Val/Val genotypes of patients, compared with in patients with type carry Ⅱe/IIe gene, its treatment effectiveness increased 6.39 times (OR=6.39, OR95% CI:1.61-25.35, P=0.008).When patients carrying GSTP1 Ue105Val Ⅱe/Val+Val/Val genotypes, the effect of chemotherapy in patients with no history of smoking is better than the Ⅱe/Ⅱe type 5.56 times(OR=5.56, OR95%CI=1.39-24.25, P<0.001). But when patients carrying Ⅱe/Val+Val/Val genotypes, the staging of patients with chemotherapy is better than Ⅱe/IV type Ⅱe 3.10 times (OR=3.10, OR95%CI=1.19-8.16, P=0.01). But when patients carrying Ⅱe/Val+Val/Val genotypes, the pathological classification of squamous carcinoma patients compared with carry Ⅱe/IIe type, treatment effect is superior to the Ⅱe/IIe type 2.92 times (OR=2.92, OR95%CI=1.12-7.70, P=0.02) Carry Ⅱe/Val+Val/Val genotypes of patients, with cisplatin+dorsey plug his plan of chemotherapy in patients than had the Ⅱe/Ⅱe patients were 4.05 times higher (OR=4.05, OR95%CI=1.06-17.10, P=0.02). Carry Ⅱe/Val+Val/Val genotypes patients, patients with cisplatin+changchun rui marina chemotherapy sensitivity is better than carry Ⅱe 3.72 times/Ⅱe type patients (OR=3.72, OR95%CI=0.96-17.10).GSTP1 11e105Val Ⅱe/Val genotypes significantly associated with survival time, Ⅱe/Val genotypes to carry a lower risk of death from non-small cell lung cancer(HR=0.36,95%CI:0.11-0.98, P=0.03).The existence of GSTM1 and lack and there was no statistically significant difference of chemotherapy sensitivity and survival time.The existence of GSTT1 gene and lack and there was no statistically significant difference of chemotherapy sensitivity and survival time. For gene XRCC1 Arg194Trp Arg280His, Arg399Gln loci Hardy-Weinberg inspection respectively, XRCC1 Arg280His genes do not conform to the Hardy-Weinberg equilibrium rule (P= 0.004), XRCClArg194Trp Arg399Gln accord with Hardy-Weinberg genetic equilibrium rule (P= 0.48, P= 0.48). Carry XRCClArg399Gln AA genotype in patients with non-small cell lung cancer chemotherapy effect is to bring a 3.69 times of GG genotype (OR= 3.69,95% CI= 1.34 10.17, P= 0.01) and carry the GA genotype of non-small cell lung cancer patients compared with the GG genotype, chemotherapy effect is no statistical differences (OR= 2.54,95% CI= 0.927.01, P= 0.07).Patients with a history of smoking carrying XRCC1 Arg399Gln GA+ AA genotype, the effect of chemotherapy is better than the GG type to carry 2.56 times (OR= 2.56, OR95% CI= 1.06 7.70, P= 0.02) carry XRCC1 Arg399Gln GA+AA genotype TNM staging of patients with stage ⅢB, the effect of chemotherapy was 3.07 times of the GG type (OR= 3.07, OR95% CI= 0.9710.07, P= 0.03).XRCC1 Arg194Trp Arg280His and Arg399Gln gene polymorphism and non-small cell lung cancer patients survival time no relationship, there was no statistically significant difference (P>0.05)Cox risk proportion model analysis, XRCC1 Arg194Trp and Arg280His and Arg399G1n gene polymorphisms and risk of non-small cell lung cancer death no correlation, there was no statistically significant difference (P>0.05) Using Logistic regression model analysis found that patients with non-small cell lung cancer at the same time carry GSTP1 11e105Val Ⅱe/Val+Val/Val and XRCC1 Arg399Gln G/A+A/A genotype chemotherapy sensitivity is at the same time carry GSTP1 lle105Val Ⅱe/Ⅱe and 4.17 times of XRCC1 GG genotype (OR= 4.17, OR95% CI:1.46 12.32, P= 0.003).Cox risk proportion model analysis found that GSTP1 11e105Val and XRCC1 Arg399Gln gene polymorphisms and risk of non-small cell lung cancer death no statistically significant difference (P> 0.05).[Conclusion]GSTM1 deletion or not with non-small cell lung cancer patients with adanced platinum drugs chemotherapy effect and no significant correlation between the survival time.GSTT1 deletion or not with non-small cell lung cancer patients with adanced platinum drugs chemotherapy effect and no significant correlation between the survival time.When patients with advanced non-small cell lung cancer GSTP1 11e105Val genes carry the Val/Val genotypes, platinum drugs chemotherapy effect effect is good Val/Val genotypes, patients with longer survival.The results of GSTP1 11e105Val gene polymorphism can enhance the curative effect of patients with non-small cell lung cancer chemotherapy. XRCC1 Arg399Gln with AA genotype from non-small cell lung cancer chemotherapy was 3.69 times carry GG genotype.XRCC1 Arg399Gln GA+AA genotype and smoking and TNM staging of non-small cell lung cancer chemotherapy sensitivity have interaction. Non-small cell lung cancer patients at the same time carry GSTP1 lle105Val Ⅱe/Val+ Val/Val and XRCC1 Arg399Gln G/A+A/A genotype can significantly increase the sensitivity of non-small cell lung cancer chemotherapy.The research did not find XRCC1 Arg280His and XRCC1 Arg194Trp gene polymorphism with advanced non-small cell lung cancer platinum drugs chemotherapy sensitivity and the risk of death.