培美曲塞联合铂类药物治疗非小细胞肺癌疗效与TYMS、GSTP1基因多态性相关性的临床研究

发布时间：2018-03-15 11:41

本文选题：非小细胞肺癌　切入点：TYMS　出处：《南华大学》2015年硕士论文　论文类型：学位论文

【摘要】：目的本文探讨了人胸苷酸合成酶(TYMS)和谷胱甘肽S转移酶P1(GSTP1)基因多态性与晚期非小细胞肺癌患者(NSCLC)对培美曲塞联合铂类方案(PP/PC方案)化疗敏感性的关系。为进一步研究培美曲塞联合铂类药物方案对NSCLC化疗敏感性指标及个体化治疗提供参考。方法在2013年1月1日-2015年1月1日的时间段内,收集并筛选出晚期NSCLC腺癌病例30例,所有病例首次化疗前抽取静脉血2m1,提取全血基因组DNA,应用实时焦磷酸测序技术检测TYMS、GSTP1基因多态性,对患者基因型进行分组。采用随访研究,探讨TYMS、GSTP1基因多态性与PP/PC方案敏感性(近期疗效、远期疗效)之间的关系。结果1.基因型检测结果:在研究病例中,GSTP1基因第105位氨基酸位点存在3种基因型,基因型分布频率分别为A/A(60%),A/G(36.3%)和G/G(3.3%)。TYMS基因根据5`UTR区存在的28bp串联重复次数分3型:2R/2R(3.3%)、2R/3R(43.4%)、3R/3R(53.3%)。2.免疫组化病例14例,其中TS蛋白阳性表达9例(64.3%),TS蛋白阴性表达5例(35.7%)。2R/2R、2R/3R为低表达组,3R/3R型为高表达组,TYMS 2R/3R基因型和TS蛋白表达存在负相关性(γ=0.757,P=0.036)。3.在单因素分析中,GSTP1(I105V)位点携带G等位基因的患者近期有效率(58.3%)显著高于A/A基因型患者(16.7%)(P0.05),携带G等位基因患者的中位PFS长于A/A基因型(5.7月vs.4.0月,P=0.047)。另外患者的年龄、分化程度、临床分期,近期疗效和PFS相关性比较无统计学差异。4.在单因素分析中,TYMS基因型与近期有效率相关性无统计学差异(P0.05),与患者PFS相关性有差异,TYMS基因型为3R/3R的患者中位PFS小于2R/3R基因型的患者(4.3月vs7.8月,P=0.036),5.COX比例风险模型多因素分析性别、基因型与PFS之间的相关性,性别和基因型都与PFS相关,其中女性的疾病进展风险是男性的2.12倍(P0.05),GSTP1(I105V)基因型为A/A的患者疾病进展风险是携带G等位基因患者的1.537倍(P0.05),TYMS基因型为3R/3R的患者疾病进展风险是2R/3R基因型患者的1.763倍(P0.05)。结论:1.晚期NSCLC患者PP/PC方案中,GSTP1(I105V)位点携带G等位基因的患者的近期疗效和PFS均高于A/A型患者;TYMS基因5`UTR区基因型为2R/3R型的患者PFS长于3R/3R型患者,更具有生存期优势。2.GSTP1(I105V)和TYMS 2R/3R基因型多态性检测结果可作为预测晚期非小细胞肺腺癌患者培美曲塞联合铂类药物方案选择的参考指标之一。3.晚期NSCLC患者外周血白细胞的TYMS(2R/3R)基因型可能反映了肿瘤细胞内TYMS酶的含量。
[Abstract]:Objective to investigate the relationship between the polymorphism of human thymidine synthase (TYMS) and glutathione S-transferase (GSTP1) gene and the chemosensitivity of advanced non-small cell lung cancer (NSCLC) to pemetrexide combined with PPP / PC regimen. To study the chemosensitivity and individualized treatment of NSCLC with pemetrexide combined with platinum regimen. Methods during the period from January 1st 2013 to January 1st 2015, 30 cases of advanced NSCLC adenocarcinoma were collected and screened. Venous blood 2ml was extracted from all patients before the first chemotherapy. The genomic DNA was extracted from the whole blood. The polymorphism of TYMS-GSTP1 gene was detected by real-time pyrosequencing technique, and the patients were divided into two groups. To investigate the relationship between the polymorphism of TYMSN GSTP1 gene and the sensitivity of PP/PC regimen. Results 1. Genotypic analysis: there were three genotypes at the 105th amino acid locus of the GSTP1 gene. The frequency of genotype distribution was as follows: a / A / A / A = A / P / G ~ (36.3) and G / G / G ~ (3.3), respectively. According to the number of 28bp tandem repeats in the 5'#en0# region, the TYMS gene was divided into 3 types: 2R / 2R / 2R / 3.3R = 43.43.4R / 3R = 53.33.30.14 cases were immunohistochemically. There was a negative correlation between TYMS 2R / 3R genotype and TS protein expression (纬 -0.757P0.036N. 3). In univariate analysis, there was a negative correlation between TYMS 2R / 3R genotype and TS protein expression (纬 0.757P0.036N. 3). In univariate analysis, there was a negative correlation between TYMS 2R / 3R genotype and TS protein expression (纬 -0.757P0.036N. 3). The recent effective rate (58.3%) was significantly higher in patients with A / A genotype than in patients with A / A genotype. The median PFS of patients with G allele was longer than that of patients with A / A genotype (5.7-month vs.4.0 month, P0.047). In addition, the age of the patients was higher than that of the patients with G allele. Degree of differentiation, clinical stage, In univariate analysis, there was no significant difference between the genotype of TYMS and the short-term effective rate (P 0.05), but there was a significant difference between the genotype and PFS. The median PFS of the patients with 3R / 3R of TYMS genotype was less than 2R / 3R. Patients with genotype (4.3-month vs7.8 month P 0.036) 5. Cox proportional risk model multivariate analysis of gender, The relationship between genotype and PFS, sex and genotype were correlated with PFS. The risk of disease progression in women was 2.12 times higher than that in men. The risk of disease progression in patients with A / A genotype was 1.537 times as high as that in patients with G allele. The risk of disease progression was 1.763 times that of patients with 2R / 3R genotype. Conclusion the short term curative effect and PFS of patients with G allele carrying G allele in PP/PC regimen of late stage NSCLC patients were higher than those of patients with 2R / 3R genotype of TYMS gene 5'#en3# region, which were longer than those of 3R / 3R patients with TYMS gene 5'#en3# region genotype, conclusion\\%\%\%\%\%\%\%\%\%\%\%\%\%\%\%\%\%\%\%\%. GSTP 1 + I105V) and TYMS 2R / 3R genotype polymorphism can be used as a reference index to predict the combination of pemetrexide and platinum regimen in patients with advanced non-small cell lung adenocarcinoma. The TYMS 2 R / 3 R genotype may reflect the content of TYMS enzyme in tumor cells.
【学位授予单位】：南华大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R734.2

【共引文献】