Associations Of DNA Repair Gene, MDR1, And PTPRD Polymorphisms With Chemothera And Survival In Lung Cancer Patients

[Objective] Lung cancer is the first leading cause of cancer-related death in China.Currently, the outcome of resection or chemotherapy for lung cancer is not satisfactory.Individualized treatment according to specific genetic background is very important forimproving outcome. One aim of this study is to investigate the association of singlenucleotide polymorphism (SNP) of a group of important genes including x-ray repaircross-complementing group1(XRCC1), excision repair cross-complementing group1(ERCC1), xeroderma pigmentosum group D (XPD), x-ray repair cross-complementinggroup3(XRCC3), breast cancer susceptibility gene1(BRCA1) and multiple drugresistance gene1(MDR1) polymorphisms with therapeutic results of the chemotherapyand survivals of lung cancer patients. We also investigated the association ofprotein-tyrosine phosphatase receptor delta gene (PTPRD) polymorphism with thesusceptivity and the prognosis of lung cancer in Chinese population, providing evidencefor early detection and prognosis prediction of this malignancy.[Methods] A total of377patients with lung cancer and754healthy controls wereenrolled in the study. DNA was isolated from peripheral bloods of the study subjects.Seven polymorphisms (XRCC1Arg399Gln，ERCC1Asn118Asn，XPD Lys751Gln，XRCC3A4541G，BRCA1Ser1613Gly，MDR1Ile1145Ile and PTPRD G4254C) weregenotyped by TaqMan method. The chemotherapeutic effect and overall survival (OS) inpatients with lung cancer were evaluated. Patients with complete response (CR), partialresponse (PR) and stable disease (SD) were defined as patients with clinical benefit, andpatients with progressive disease (PD) were defined as patients without clinical benefit.Associations between polymorphisms and lung cancer risk or chemotherapeutic effectwere estimated using χ2test and unconditional logistic regression model. Associationsbetween polymorphisms and OS were estimated using Kaplan-Meier methods andLog-rank test for univariate analysis and Cox proportional hazards model for multivariateanalysis.[Results]1. BRCA1Ser1613Gly and MDR1Ile1145Ile significantly correlated withchemotherapeutic effect in advanced non-small cell lung cancer (NSCLC) patients. TheBRCA1G allele carriers (AG+GG) and the MDR1T allele carriers (CT+TT) had betterclinical benefit than wild type carriers (P=0.013, P=0.045, respectively). No significantassociations were found between ERCC1Asn118Asn, XPD Lys751Gln, XRCC1 Arg399Gln or XRCC3A4541G and clinical benefit. Furthermore, we found that the6polymorphisms had interaction in the drug response, a greater number of variant alleles(XRCC1A, ERCC1T, XPD C, XRCC3G, BRCA1G or MDR1T) was associated withbetter clinical benefit (P=0.024).2. Advanced NSCLC patients treated with chemotherapy with BRCA1G allele (AG+GG)had a significantly better OS compared with advanced NSCLC patients with AA genotype(Hazard Ratio [HR]=0.617,95%CI=0.402-0.948, P=0.028). Stratified advanced NSCLCpatients according to clinical characters, BRCA1AG+GG genotype was significantlyassociated with better OS among advanced NSCLC patients with squamous cell carcinoma,smoking habit, performance status1, and stage III (Log-rank P<0.05); XRCC1GA+AAgenotype was significantly associated with better OS among advanced NSCLC patientswith adenocarcinoma (Log-rank P=0.038，HR=0.496，95%CI=0.246-0.997).3. Postoperative early-stage NSCLC patients with ERCC1TT genotype had a significantlyworse OS compared with early-stage NSCLC patients with CC+CT genotype (HR=3.087，95%CI=1.197-7.961，P=0.020). Stratified early-stage NSCLC patients according toclinical characters, XPD AC genotype was significantly associated with worse OS amongearly-stage NSCLC patients with stage III and squamous cell carcinoma (Log-rankP=0.016,0.008, respectively); XRCC1GA+AA genotype was significantly associated withbetter OS among early-stage NSCLC patients with stage III and adjuvant chemotherapy(Log-rank P=0.004,0.050, respectively).4. PTPRD G4254C was significantly associated with the risk of lung cancer, GC+CCgenotype had a significantly increased lung cancer risk compared with GG genotype(P=0.039, OR=1.298,95%CI=1.013-1.663). Similar association existed in smokers(ajusted OR=1.563，95%CI=1.013-2.412). In total, no significant associations were foundamong PTPRD G4254C and both chemotherapeutic effect and OS. Stratified postoperativeearly-stage NSCLC patients according to clinical characters, PTPRD CC genotype wassignificantly associated with worse OS among female patients, adenocarcinoma patientsand stage I patients (Log-rank P=0.014,0.009,0.000, respectively).[Conclusion] BRCA1Ser1613Gly and MDR1Ile1145Ile may affect the response ofadvanced NSCLC patients to chemotherapy. It can be useful to research combinations ofSNPs for customizing chemotherapy. BRCA1Ser1613Gly may be important prognosticmarker in advanced NSCLC patients treated with chemotherapy, and ERCC1Asn118Asnmay be important prognostic marker in early-stage NSCLC patients treated with operation. PTPRD G4254C polymorphism is significantly associated with a higher risk of developinglung cancer, but does not significantly affect chemotherapeutic effect and OS in lungcancer patients.