转化生长因子-β1基因多态性与食管鳞癌患者放疗和化疗疗效及生存的关系

The association between polymorphism of transforming growth factor-β1 and radiochemotherapy response and survival in esophageal squamous cell carcinoma patients

目的探讨转化生长因子-β1（transforming growth factor—β1，TGF-β1）基因-509C／T多态性与食管鳞癌患者放疗和化疗疗效及生存的关系。方法应用聚合酶链式反应．限制性片段长度多态（polymerase chain reaction—based restriction fragment length polymorphism，PCR-RFLP）方法，检测了230例接受单纯放疗或放疗合并化疗的食管鳞癌患者TGF-β1基因-509C／T位点的基因型。采用非条件logistic回归模型计算OR值和95％CI值，评价各基因型与食管鳞癌患者放疗和化疗疗效相关性，并用单因素和多因素Cox回归模型计算不同基因型、不同临床参数与食管鳞癌放疗和化疗患者生存时间、死亡风险（HK）的关系。结果在208例有上消化道造影疗效评价的患者中，87例对放疗和化疗敏感，其中TGF-β1基因-509CC、CT和TT基因型分别有17例（19．5％）、48例（55．2％）和22例（25．3％）；在对放疗和化疗不敏感的121例患者中，3种基因型分别有39例（32．2％）、54例（44．6％）和28例（23．2％）。与携带TGF-β1基因-509CC基因型的患者相比，携带至少1个T等位基因的患者（CT或TT基因型）对放疗和化疗更敏感，校正OR值为2．07（95％CI：1．05～4．09；P=0．036）。携带CC基因型患者的中位生存时间是17．0（95％CI：12．0～23．0）个月，CT基因型患者是22．0（95%CI：16．0～33．0）个月，TT基因型患者是25．0（95％CI：15．0—41．0）个月。与CC基因型患者比较，CT和TT基因型患者生存时间差异接近统计学临界水平（P=0．063）。与携带CC基因型患者相比，携带CT和TT基因型患者的HR有降低的趋势，校正HR值分别是0．81（95％CI：0．52—1．24）和0．86（95％CI：0．65～1．12），但差异无统计学意义（P〉0．05）。肿瘤部位、肿瘤临床分期、放疗和化疗疗效对食管鳞癌放疗和化疗患者的HR产生明显影响[校正HR值分别是1．28（95％CI：1．01～1．61，P=0．040）、1．49（95％CI：1．17～1．88，P=0．001）、1．55（95％CI：1．06～2．26，P=0．023）]。结论TGF-β1基因-509C/T多态性与食管鳞癌放疗和化疗疗效相关，可能是预测放疗和化疗疗效的遗传标志。

Objective To evaluate the association between polymorphism of transforming growth factor-β1 （ TGF- β1 ） - 509C/T and radiochemotherapy response and survival in esophageal squamous cell carcinoma（ESCC） patients. Methods The genotype of TGF-β1 -509C/T was detected by polymerase chain reaction-based restriction fragment length polymorphism assay （ PCR-RFLP ） in 230 ESCC patients receiving radiotherapy alone or in combination with chemotherapy. Unconditional multivariate logistic regression analysis was done to estimate adjusted odds ratios （ORs）along with the corresponding 95% confidence intervals （ Cls ） for the polymorphism and radiochemotherapy response. The associations between overall survival time or hazard ratio （HR） of ESCC patients and genetic variation or the clinical data were estimated by applying univariate and multivariate Cox-regression analyses. Results Among 208 patients with upper gastrointestinal contrast assessment,87 cases were susceptible to radiochemotherapy treatment and the TGF -β1 - 509CC, CT and TT genotype patients were 17 （ 19. 5% ）, 48 （ 55.2% ） and 22 （ 25.3% ）, respectively. Among the patients who were insensitive to radiochemotherapy treatment（ n = 121 ） , the TGF-β1 - 509CC, CT and TT genotype patients were 39 （32.2%）, 54 （44.6%） and 28 （23.2%）, respectively. Compared with TGF-β1 -509CC genotype, the CT and TF genotype carriers had a significantly better treatment response（ adjusted OR = 2. 07,95% CI, 1.05 -4. 09, P = 0. 036 ）. The median survival time of CC genotype patients was 17.0 （95 % CI, 12. 0 -23.0） months, CT genotype patients was 22. 0 （95 % CI, 16.0 -33.0） months and ＇IF genotype patients was 25.0（95% CI,15.0 -41.0） months. Compared to CC genotype patients,the survival time difference of CT and TT group was close to the statistical break point （ P = 0. 063 ）. Our data showed that the subjects with CT or TT genotype had an decreased HR respectively as compared with those with CC genotype （CT, adjusted HR = 0. 81,95% CI, 0. 52 - 1.24; TT, adjusted HR = 0. 86,95% CI,0. 65 -1.12） ,but the difference was not statistically significant（ P 〉 0. 05 ）. However, tumor location, clinical stage and radiochemotherapy response affected the overall survival time of the patient significantly （ adjusted HR = 1. 28,95 % CI： 1.01 - 1.61, P = 0. 040 ; 1.49,95 % CI,1.17 - 1.88, P = 0. 001 ; 1.55,95% CI, 1.06 - 2. 26, P = 0. 023, respectively ） . Conclusion These results suggest that TGF-β1 -509C/T polymorphisms were associated with radiochemotherapy for esophageal squamous cell carcinoma which might be genetic markers for prediction of the radiochemotherapy response in ESCC patients.