Clinical And Laboratory Study On Factors Associated With Radiation-induced-Lung-Injury And Survival Of Lung Cancer Patients

PartⅠ: Predicting effect of single nucleotide polymorphisms with radiation-induced pneumonitisObjective: The objective is to examine the relationship between genetic polymorphisms in DNA repair, apoptosis and inflammatory cytokine genes with radiation-induced pneumonitis (RP) in patients with lung cancer.Materials and methods: Between January 2004 and August 2006, 127 non-small cell lung cancer and 43 small cell lung cancer patients underwent thoracic radiotherapy were enrolled in this study. The primary endpoint was≥grade 2 RP according to NCI CTC3.0 criteria. We analyzed 35 genetic variations in 18 DNA repair, apoptosis and inflammatory cytokine genes including ATM, P53, XRCC3, NBS1, XRCC1, ADPRT, ERCC1, XPD, XPC, XPG, ZNF350, FAS, FASL, CASP8, COX-2, TGF-β1, CD14, and ACE by PCR-based restricted fragment length polymorphism (RFLP) method.Results: With a median follow-up of 22 months, 29 patients (17.1%) experienced≥grade 2 pneumonitis and the median occurrence time was 59 days from the first day of irradiation. Significant association with pneumonitis was found for some clinical factors as concurrent chemotherapy and mean lung dose. ATM -111A allele (ATM -111G/A, rs 189037) was independently associated with the risk of RP (HR = 3.27, 95% CI = 1.09 -9.78, P = 0.034). P53 72Pro allele (P53 Arg72Pro, rs 1042522) tended to have a low risk of RP (HR = 0.43, 95% CI = 0.17 - 1.12, P = 0.084). Furthermore, the presence of P53 72Arg/Arg genotype could enhance the predictive effect of ATM-111A allele for RP (HR = 4.75, 95% CI = 1.33 - 17.04, P = 0.017).Conclusion: Genetic polymorphisms in the ATM and P53 genes may be predictive factors to the risk of RP in lung cancer patients with radiotherapy. PartⅡ: Association of single nucleotide polymorphisms with radiation-induced esophagitisObjective: To evaluate the relationship between single nucleotide polymorphism (SNP) in candidate genes with radiation-induced esophagitis in patients with lung cancer.Materials and methods: One hundred and seventy patients with pathologically diagnosed lung cancer were enrolled in this study from Jan. 2004 to Aug. 2006. The total target doses were between 45 Gy and 70 Gy (median 60Gy). One hundred and thirty-two patients were treated with three-dimensional conformal radiotherapy (3D CRT) and 38 patients with two-dimensional radiotherapy (2D RT). Thirty-seven patients received radiotherapy alone, 82 patients received sequential chemoradiation and 51 patients received concurrent chemoradiation. Thirty-five SNPs in 18 DNA repair were analyzed by using PCR-based RFLP. The endpoint was grade >2 radiation-induced esophagitis.Results: Forty of the 170 patients developed radiation-induced esophagitis of grade≥2, with 36 patients in grade 2 and 4 patients in grade 3. Univariate analysis revealed that radiation technique and concurrent chemoradiation were statistical significant relative to the incident of esophagitis (P = 0.032,0.049), and both of them had the trend to associate with the esophagitis (P = 0.072,0.094). An increased incidence of esophagitis was observed associating with the TGF-β1 -509T allele (rs 1800469) and XPD 751Lys/Lys (rsl3181) genotypes (χ~2 = 5.651 P = 0.017;χ~2 = 3.837 P = 0.048) in multivariate analysis.Conclusion: Genetic polymorphisms in TGF-β1 gene and XPD gene have a significant association with radiation-induced esophagitis. PartⅢ: Single nucleotide polymorphisms and outcome of local advanced non-small cell lung cancer patients treated with radiotherapyObjective: To examine the possible relationship between SNPs in candidate genes with outcomes of local advanced non-small cell lung cancer (NSCLC) treated with radiotherapy.Methods and Materials: 105 non-small cell lung cancer patients who were inoperable and underwent thoracic radiotherapy were evaluated. We analyzed 35 SNPs in 18 DNA repair, apoptosis and inflammatory cytokine genes using RFLP analysis. The primary endpoint of the study was to investigate the association between genotypes and survival. The Kaplan-Meier method and log-rank test were used to assess the prognostic significance of the clinical factors and genotypes for survival. Cox forward-stepwise regression model was chosen to assess genetic risk factors in multivariate analyses.Results: Median age was 60 years (rang, 26 to 83 years), and there were 68 deaths. All the patients diagnosed stageⅢwith a median follow-up of 26 months were evaluated. Of these patients, 25 were stageⅢa and 80 were stageⅢb. The 1-, 2-, 3-, 4-year overall survival and the median survival were 77.6%, 40.0%, 24.9%, 10.7% and 29.1 months; the 1-, 2-, 3-, 4-year loco-regional progression-free survival and the median survival were 72.2%, 53.1%, 37.8%, 37.8% and 25.3 months, and the 1-, 2-, 3-, 4-year metastasis progression-free survival and the median survival were 57.5%, 47.5%, 38.0%, 38.0% and 16.8 months. At univariate analysis, the overall survival received benefit from KPS, 3D CRT, pre-RT pulmonary function and ATM 81165T/C (rs4988044). Multivariate Cox regression analysis identified the ATM 81165C allele (ATM 81165TC and 81165CC genotypes) as an independent prognostic risk factor (HR = 1.939; P = 0.034; adjusted for KPS, radiation technique and type of treatment). ERCC1 4855C/T (rs3212961) was the only fact that significantly associated with loco-regional progression-free survival and the variant alleles were associated with shorted survival (HR = 2.875; P = 0.031). XRCC1 Arg399Gln (rs25487) had marginal significantly associated with metastasis progression-free survival (HR = 0.539; P = 0.051).Conclusions: Genetic polymorphism in the ATM, ERCC1 and XRCC1 may be prognostic factors in local advanced NSCLC patients treated with radiotherapy.