外周血TYMS基因多态性与晚期肺腺癌患者对含培美曲塞化疗方案疗效的相关性研究

发布时间：2018-06-08 03:12

  本文选题：肺腺癌 + 胸苷酸合成酶TYMS　； 参考：《大连医科大学》2017年硕士论文

【摘要】：目的:培美曲塞(pemetrexed,PEM)于2004年首次被美国食品与药品管理局(food and drug administration,FDA)批准为治疗恶性胸膜间皮瘤的临床一线化疗药。随后的研究表明培美曲塞在治疗晚期非鳞状非小细胞肺癌,可同样使患者受益。培美曲塞作为一类多靶点的化疗药物,能够明显降低胸苷酸合成酶(Thymidylate synthase,TS)、二氢叶酸还原酶(Dihydrofolate reductase,DHFR)及甘氨酸胺核苷酸甲酰基转移酶(Glycinamide ribonucleotide formyl transferase,GARFT)等细胞合成代谢相关酶的活性,从而达到降低肿瘤细胞恶性增殖的效果。许多实验室研究及临床研究证据表明,TYMS作为TS的基因形式,其多态性会直接影响TS的表达水平,从而造成恶性肿瘤患者对培美曲塞的化疗敏感性的不同。然而TYMS基因多态性在预测含培美曲塞化疗方案治疗晚期肺腺癌敏感程度的临床价值方面仍有争议。本研究通过对我院晚期肺腺癌患者外周血中TYMS基因的多态性分布及其与培美曲塞化疗疗效的关系分析,旨在了解晚期肺腺癌患者外周血TYMS基因多态性对含培美曲塞化疗方案疗效的指导意义。同时结合患者临床资料,分析不同临床病理参数对TYMS基因多态性及培美曲塞化疗疗效的影响,最终完善晚期肺腺癌患者的个体化治疗模式。方法:收集大连医科大学附属第一医院2010年1月1日至2015年12月31日,经影像学及病理学明确诊断为晚期(ⅢB期及Ⅳ期)肺腺癌的患者56例。患者在化疗前均采集了外周静脉血,使用血全基因组DNA提取试剂盒(Solarbio,D1800,Beijing)提取基因组DNA,采用聚合酶链反应(PCR)扩增,利用2%琼脂糖凝胶检测PCR扩增产物,分析TYMS基因5' UTR长度多态性。TYMS基因型结果分析分别为116 bp的2R/2R,144 bp的3R/3R以及同时包含116 bp和144 bp的2R/3R。此56例患者均接受了含培美曲塞的双药联合化疗方案(培美曲塞+顺铂或培美曲塞+卡铂),3周为一周期。化疗期间,每2周期进行一次影像学疗效评价;化疗后,每2个月评价一次。随诊患者至2017年1月1日。记录所有患者的临床病理参数,包括患2者的年龄、性别、肿瘤分期、ECOG评分、吸烟状况及TYMS基因多态性。应用SPSS20.0统计软件分析各临床病理参数与TYMS基因多态性及疾病控制率(disease control rate,DCR)的相关性,同时比较TYMS基因多态性和患者无进展生存时间(progression-free survival,PFS)及总生存时间(overall survival,OS)的关系。结果:1.56例晚期肺腺癌患者年龄分布于32-80岁,中位年龄61岁;男性患者32人,女性患者24人;临床分期ⅢB期22人,Ⅳ期34人;ECOG评分0分16人,1分31人,2分9人;吸烟者25人,不吸烟者31人。利用RECIST 1.1评分标准评分,其中完全缓解(CR)0人,部分缓解(PR)19人,病变稳定(SD)21人,疾病进展(PD)16人,疾病控制率DCR(CR+PR+SD)为71.43%。2.TYMS5'UTR基因多态性中,2R/3R基因型患者23例,占41.1%,3R/3R型患者19例,占33.9%,2R/2R患者14例,占25%。3.56例患者性别、年龄、临床分期、ECOG评分及吸烟状况与TYMS 5'UTR基因多态性之间无相关性(P0.05),研究同时显示以上临床病理参数与接受培美曲塞化疗的肺腺癌患者DCR之间也无相关性(P0.05)。4.2R/2R+2R/3R组患者的DCR明显优于3R/3R组患者(P0.05),2R/2R+2R/3R 组患者 PFS 显著长于 3R/3R 组(P0.001)。5.2R/2R+2R/3R组患者较3R/3R组的OS较长,但二者比较无统计学意义(P=0.10)。结论:1.晚期肺腺癌患者外周血胸苷酸合成酶TYMS基因多态性中,2R/3R及3R/3R基因型较多,2R/2R基因型较少。2.TYMS 2R/2R和2R/3R基因型患者接受培美曲塞化疗的DCR较3R/3R基因型患者显著增高,PFS较3R/3R基因型患者显著延长。3.TYMS 2R/2R和2R/3R基因型患者接受培美曲塞化疗的OS较3R/3R基因型患者延长,但二者在统计学无显著差异。4.TYMS基因型可作为预测晚期肺腺癌患者培美曲塞化疗疗效的敏感指标。
[Abstract]:Objective: pemetrexed (PEM) was first approved by the US Food and Drug Administration (food and drug administration, FDA) for the first line of clinical chemotherapy for the treatment of malignant pleural mesothelioma in 2004. Subsequent studies showed that pemetrexed could benefit from patients with advanced non-squamous non-small cell lung cancer as well. Pemetrexed was used as a patient. A class of multitarget chemotherapy drugs can significantly reduce the activity of Thymidylate synthase (TS), dihydrofolate reductase (Dihydrofolate reductase, DHFR) and glycine amine nucleotide Methoyl transferase (Glycinamide ribonucleotide formyl transferase, GARFT), and thus reduce the activity of metabolic related enzymes. The effect of malignant proliferation of tumor cells. Many laboratory and clinical evidence suggest that TYMS is a genetic form of TS, and its polymorphism will directly affect the level of TS expression, resulting in different sensitivity to pemetrexed chemotherapy in patients with malignant tumor. However, the polymorphism of TYMS gene is expected to be late in the treatment of pemetrexed chemotherapy. The clinical value of the sensitivity of lung adenocarcinoma is still controversial. In this study, the relationship between the polymorphism distribution of TYMS gene in peripheral blood and the effect of pemetrexed chemotherapy on the peripheral blood of patients with advanced lung adenocarcinoma was analyzed. The purpose of this study was to understand the guidance of the TYMS gene polymorphism of peripheral blood in patients with advanced lung adenocarcinoma for the therapeutic effect of pemetrexed chemotherapy. The effect of different clinicopathological parameters on TYMS gene polymorphism and pemetrexed chemotherapy was analyzed combined with the clinical data of patients. Finally, the individualized treatment mode of patients with advanced lung adenocarcinoma was perfected. Methods: the First Affiliated Hospital of Dalian Medical University was collected from January 1, 2010 to December 31, 2015 by imaging and pathology. 56 patients were diagnosed as advanced (stage III B and IV) lung adenocarcinoma. The peripheral venous blood was collected before chemotherapy, genomic DNA was extracted from the whole genome DNA Extraction Kit (Solarbio, D1800, Beijing), and polymerase chain reaction (PCR) was used to amplify and detect PCR amplification products with 2% agarose gel, and the TYMS gene 5'UTR length was analyzed. The results of polymorphic.TYMS genotype analysis were 116 BP 2R/2R, 144 BP 3R/3R, and 2R/3R. with 116 BP and 144 BP respectively. All the 56 patients received pemetrexed double drug combination chemotherapy (pemetrexed + cisplatin or pemetrexed + carboplatin), 3 weeks as one cycle. During the period of chemical treatment, an image evaluation was conducted every 2 cycles. After chemotherapy, the patients were evaluated every 2 months. The patients were followed up to January 1, 2017. The clinicopathological parameters of all patients were recorded, including age, sex, tumor staging, ECOG score, smoking status and TYMS gene polymorphism. The SPSS20.0 statistical software was used to analyze the clinical parameters and TYMS gene polymorphism and disease control rate (disease). The correlation between control rate, DCR) and the relationship between the TYMS gene polymorphism and the patient's progression free survival time (progression-free survival, PFS) and the total survival time (overall survival, OS). Results: 1.56 patients with advanced lung adenocarcinoma were aged 32-80 years, the median age was 61 years, 32 men and 24 women, and clinical stage III. Period B 22, stage IV 34; ECOG score 0 points 16 people, 1 points 31 people, 2 minutes and 9 people, 25 smokers and 31 non smokers, using the RECIST 1.1 score standard, including complete remission (CR) 0, PR 19, disease progression (PD) persons, disease control rate DCR (CR+PR+SD) as 71.43%.2.TYMS5'UTR gene polymorphism, 2R/3R basis 23, 41.1%, 19, 33.9%, and 14 2R/2R patients in 3R/3R patients, accounting for sex, age, clinical stage, ECOG score, smoking status and TYMS 5'UTR gene polymorphism (P0.05). The study also showed that the above clinical parameters were also between the DCR patients receiving pemetrexed chemotherapy and DCR of the lung adenocarcinoma patients. The DCR of patients with no correlation (P0.05).4.2R/2R+2R/3R was significantly better than that in group 3R/3R (P0.05), and PFS in group 2R/2R+2R/3R was longer than that of 3R/3R group (P0.001).5.2R/2R+2R/3R group. The OS was longer than that of 3R/3R group, but there was no significant difference between the two groups. Conclusion: the polymorphism of peripheral thymside synthase synthetase gene polymorphism in the 1. late stage lung adenocarcinoma patients In sex, the genotype of 2R/3R and 3R/3R is more, and the DCR in the 2R/2R genotype less.2.TYMS 2R/2R and 2R/3R genotype patients receiving pemetrexed chemotherapy is significantly higher than that of the 3R/3R genotype patients. PFS is significantly longer than the 3R/3R genotype patients to prolong the.3.TYMS 2R/2R and the patients receiving pemetrexed chemotherapy longer than those of the 3R/3R genotype, but two There was no significant difference between the two groups..4.TYMS genotype can be used as a sensitive indicator for predicting the efficacy of pemetrexed in advanced lung adenocarcinoma.
【学位授予单位】：大连医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2
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本文编号：1994159