| Backgrounds and objective According to the data of National Cancer Cencer,esophageal carcinoma was diagnosed in nearly 477,900 individuals in China alone in 2015.Esophageal squamous cell carcinoma(ESCC)represents approximately 95% of all cases of esophageal cancer in the Chinese population.Radiotherapy(RT),alone or in combination with chemotherapy is the mainstay for the management of locally advanced ESCC.With the development of 3-dimensional radiation therapy and intensity modulated radiation therapy,an improved overall survival and local control rate were achieved.However,radiation pneumonitis(RP)remains a significant barrier to elevated radiation doses and can substantially compromise the quality of life.Single nucleotide polymorphisms(SNPs),recognized as biological genetic markers,have been reported to participate in many biological processes.Recent studies have also identified SNPs of candidate genes involved in DNA damage repair,pro-inflammatory responses,and oxidative stress are potential biomarkers for RP.RT causes cytotoxicity through direct ionization of normal tissues and a combination of free radicals,such as reactive oxygen species(ROS)formed by radiolysis of water.These our body possesses the ability to restore the damage by DNA repair pathways.The imbalance of the two systems will finally result in the radiation pneumonitis.In view of the above mentioned,we therefore depended on the existing literature by screening for an association of functional SNPs in SOD2,GSTP1,GSTA1 and MTHFR genes with the risk of RP in a prospective cohort of ESCC patients treated with definitive RT.Methods 1.A total of 265 initially diagnosed locally advanced esophageal squamous cell carcinoma patients receiving radiotherapy were prospectively enrolled.The status of radiation pneumonitis was evaluated and graduated by three radiation oncologists according to Common Terminology Criteria for Adverse Events 4.0,(CTCAE 4.0),and then patients were divided into two groups: the group of radiation pneumonitis(? grade 2)and the group of non-radiation pneumonitis(grade 0 and grade 1).2.A 5ml whole-blood sample was obtained from each patients before RT,and genomic DNA was isolated from the whole-blood samples using AxyPrep Blood Genomic DNA Miniprep Kit(Axygen,USA).Genotyping was performed by Sequenom Mass Array System(San Diego,USA)on known functional SNPs for candidate genes in ROS metabolism and DNA repair pathways.3.The information about patients,tumors and treatment were also collected.4.Hazard ratios(HRs)and 95% confidence intervals(CIs)were calculated by the Cox proportional hazards model.In addition,a multivariate Cox regression analysis was performed to adjust for other covariates.Kaplan–Meier analysis was used to evaluate the cumulative RP probability.All statistical tests were carried out with a two-sided P<0.05 level.Results 1.Clinical characteristics and RP status: The present study included a total of 265 ESCC patients(207 males and 58 females),with a mean age of 65 years(range from 18 to 91).All patients were part of the Chinese Han population.Among the 265 patients,30.6% had pulmonary emphysema,22.6% had hypertension,6.8% had diabetes,and 72.1% were treated with a combination of chemotherapy and RT.At the time of final analysis,the mean follow up time was 15.4 months(range: 1.3 to 24 months).Of the 265 patients,42(15.8%)developed ? 2 RP.2.Clinical characteristics and RP: In the present study,MLD and V20 were found to be significantly associated with ? 2 RP in both univariate and multivariate analyses(MLD: HR=0.186,95% CI=0.086-0.403,P<0.001,HR=0.205,95% CI=0.092-0.455,P<0.001;V20: HR=0.253,95% CI=0.112-0.570,P=0.001,HR=0.261,95% CI=0.115-0.594,P=0.001,respectively).Tumor location,stage,and chemotherapy were also found to be statistically significant in univariate analyses(HR=0.438,95% CI=0.195-0.987,P=0.046;HR=0.303,95% CI=0.102-0.901,P=0.032;HR=2.434,95% CI=1.026-5.778,P=0.044,respectively);however,these differences were not significant in multivariate analyses.3.Genetic variants and RP: We found that rs1801131 of MTHFR was significantly related to the risk of ? 2 RP(HR=0.285,95% CI=0.120-0.676,P=0.004).Similar results were also observed in multivariate analyses,after adjusting for tumor location,stage,chemotherapy and V20.(HR=0.339,95% CI=0.137-0.839,P=0.019).The other genotypes had no significant associations with the risk of ? 2 RP in this study.Conclusions We identified that both MLD and V20 were risk factors of radiation pneumonitis.In addition,rs1801131 of MTHFR gene in DNA repair pathway was statistically associated with ? 2 RP.Compared with TT,GG/GT genotype were closely associated with a lower risk.The new genetic biomarkers,combined with traditional dose parameters,will surely contribute to clinical individualized radiation therapy. |
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