6-MP代谢TPMT基因多态性与儿童ALL相关性研究

发布时间：2018-05-17 05:11

本文选题：TPMT + 基因多态性　；参考：《昆明医科大学》2017年硕士论文

【摘要】：[目的]研究昆明医科大学附属儿童医院收治的汉族急性淋巴细胞白血病(ALL)患儿巯嘌呤甲基转移酶(thiopurineS-methyltransferase,TPMT)常见的基因突变类型及其突变频率,并通过分析汉族ALL患儿维持治疗期间相应临床资料,探讨6-疏基嘌呤(6-mercaptopurine,6-MP)所导致的不良反应与TPMT基因多态性之间的关系,以期进一步指导巯嘌呤临床应用,为ALL的个体化治疗提供新的理论依据。[方法]运用等位基因特异性的PCR (AS-PCR)方法和聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测满足入选标准的93例初诊汉族ALL患儿常见TPMT突变型等位基因TPMT*2(G238C)、TPMT*3B (G460A)以及TPMT*3C(A719G)的突变情况。分析患儿维持化疗期间不良反应与其TPMT基因多态性和6-MP所致不良反应之间的关系。[结果]1.入组的93例汉族ALL患儿TPMT*3C基因发生突变者有2例,均为B系ALL患儿,突变率为2.15% (2/93),均为杂合突变;等位基因突变频率为1.08%;未检出TPMT*2、*3B基因突变。2.维持化疗期间ALL患儿6-MP累计治疗时间336.5天(55～663天),31.71%患儿(26/82)因6-MP重度不良反应暂时停药,停药的平均天数8天(2～21天);骨髓抑制继发感染者24.39%(20/82),其中7例需输注红细胞,4例需输注血小板。3.在6-MP不良反应中,白细胞减少57.32%(47/82),中性粒细胞减少59.76%(49/82),血红蛋白下降58.54% (48/82),血小板减少29.27% (24/82),谷丙转氨酶升高42.68% (35/82),谷草转氨酶升高29.27% (24/82),直接胆红素升高10.98% (9/82),胃肠道反应 12.20% (10/82)。4.在6-MP不良反应中,白细胞减少、中性粒细胞减少、血红蛋白下降、血小板减少及转氨酶升高是常见的不良反应,其中白细胞及中性粒细胞减少以重度不良反应为主,余均以轻度不良反应为主。5. TPMT*3C基因型突变的2例患儿均出现严重不良反应,2例患儿均出现明显的6-MP剂量不耐受,1/6标准剂量仍出现白细胞、中性粒细胞减少。[结论]1. 2例ALL患儿存在TPMT*3C基因突变。2. 6-MP维持治疗期间最主要的近期不良反应为骨髓抑制,主要导致白细胞、中性粒细胞减少,发生率分别是57.32%、59.76%。3. TPMT*3C基因突变的敏感性低,阳性率低,不适合中国人群作为6-MP不良反应的相关检测基因,应继续寻找其他适合中国人群的巯嘌呤敏感基因。4.现研究发现 TPMT* 2、TPMT* 3A、TPMT* 3B 和 TPMT* 3C 为最常见的基因突变类型,在本研究中仅发现TPMT*3C基因突变,此基因突变与6-MP不耐受密切相关。
[Abstract]:[objective] to study the common gene mutation types and mutation frequency of thiopurine S-methyltransferase TPMTin children with acute lymphoblastic leukemia (ALL) treated in affiliated Children's Hospital of Kunming Medical University. The relationship between TPMT gene polymorphism and adverse reactions induced by 6-spary purine 6-mercaptopurine 6-MP1 was investigated by analyzing the clinical data of ALL patients in Han nationality during maintenance therapy, in order to further guide the clinical application of captopurine. To provide a new theoretical basis for individualized treatment of ALL. [methods] Allele-specific PCR AS-PCR and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to detect the common TPMT allele TPMT-2C238Cp3B / G460A in 93 newly diagnosed Han children with ALL by polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP). And TPMT3 CX A719G). The relationship between adverse reactions during maintenance chemotherapy and TPMT gene polymorphisms and adverse reactions induced by 6-MP in children was analyzed. [result] 1. There were 2 cases of TPMT*3C gene mutation in 93 children with ALL in Han nationality. The mutation rate was 2.15% / 93% and allelic mutation frequency was 1.08%. During the maintenance of chemotherapy, the cumulative treatment time of 6-MP in ALL children was 336.5 days, 55.663 days or 31.71% of the children (26 / 82). The drug was temporarily stopped because of severe adverse reactions of 6-MP. The average day of stopping drug was 8 days and 21 days respectively, and that of the secondary infection with bone marrow suppression was 24.39 / 82 / 20 / 82, of which 7 cases needed to be infused with red blood cells and 4 cases needed to be infused with platelets. In the adverse effects of 6-MP, leukopenia 57.32% 47 / 82, neutropenia 59.76% 49 / 82, hemoglobin 58.54%, thrombocytopenia 29.27% 24 / 82, alanine aminotransferase 42.68% / 35 / 82, alanine aminotransferase 29.27% / 35 / 82, glutamic oxaloacetic transaminase 29.27% / 24 / 82, direct bilirubin 10.98% / 82N, gastrointestinal reaction 12.20% / 10 / 82a. In the adverse reactions of 6-MP, leukopenia, neutropenia, hemoglobin, thrombocytopenia and elevated aminotransferase are common adverse reactions. The rest were mainly mild adverse reactions. Severe adverse reactions were found in 2 cases of TPMT*3C genotype mutation. Significant dose intolerance of 6-MP was found in 2 cases, and leukocyte and neutropenia were still found at the standard dose of 1 / 6 of 6-MP. [conclusion] 1. The mutation of TPMT*3C gene was found in 2 cases of ALL. The main short-term adverse reaction during 6-MP maintenance therapy was bone marrow suppression, which mainly resulted in leukopenia and neutropenia, the incidence of which was 57.32 and 59.76.3. The mutation of TPMT*3C gene has low sensitivity and low positive rate, so it is not suitable for the Chinese population to be used as a related gene for the detection of 6-MP adverse reactions. Therefore, we should continue to search for other captopurine sensitive genes. 4. In this study, we found that TPMT * 2, TPMT * 3A, TPMTT * 3B and TPMT * 3C were the most common gene mutations, only TPMT*3C gene mutations were found in this study, this gene mutation is closely related to 6-MP intolerance.
【学位授予单位】：昆明医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R733.71

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