本文選題：TPMT + 基因多態(tài)性�。� 參考：《昆明醫(yī)科大學(xué)》2017年碩士論文

【摘要】：[目的]研究昆明醫(yī)科大學(xué)附屬兒童醫(yī)院收治的漢族急性淋巴細(xì)胞白血病(ALL)患兒巰嘌呤甲基轉(zhuǎn)移酶(thiopurineS-methyltransferase,TPMT)常見(jiàn)的基因突變類型及其突變頻率,并通過(guò)分析漢族ALL患兒維持治療期間相應(yīng)臨床資料,探討6-疏基嘌呤(6-mercaptopurine,6-MP)所導(dǎo)致的不良反應(yīng)與TPMT基因多態(tài)性之間的關(guān)系,以期進(jìn)一步指導(dǎo)巰嘌呤臨床應(yīng)用,為ALL的個(gè)體化治療提供新的理論依據(jù)。[方法]運(yùn)用等位基因特異性的PCR (AS-PCR)方法和聚合酶鏈反應(yīng)-限制性片段長(zhǎng)度多態(tài)性(PCR-RFLP)方法檢測(cè)滿足入選標(biāo)準(zhǔn)的93例初診漢族ALL患兒常見(jiàn)TPMT突變型等位基因TPMT*2(G238C)、TPMT*3B (G460A)以及TPMT*3C(A719G)的突變情況。分析患兒維持化療期間不良反應(yīng)與其TPMT基因多態(tài)性和6-MP所致不良反應(yīng)之間的關(guān)系。[結(jié)果]1.入組的93例漢族ALL患兒TPMT*3C基因發(fā)生突變者有2例,均為B系A(chǔ)LL患兒,突變率為2.15% (2/93),均為雜合突變;等位基因突變頻率為1.08%;未檢出TPMT*2、*3B基因突變。2.維持化療期間ALL患兒6-MP累計(jì)治療時(shí)間336.5天(55～663天),31.71%患兒(26/82)因6-MP重度不良反應(yīng)暫時(shí)停藥,停藥的平均天數(shù)8天(2～21天);骨髓抑制繼發(fā)感染者24.39%(20/82),其中7例需輸注紅細(xì)胞,4例需輸注血小板。3.在6-MP不良反應(yīng)中,白細(xì)胞減少57.32%(47/82),中性粒細(xì)胞減少59.76%(49/82),血紅蛋白下降58.54% (48/82),血小板減少29.27% (24/82),谷丙轉(zhuǎn)氨酶升高42.68% (35/82),谷草轉(zhuǎn)氨酶升高29.27% (24/82),直接膽紅素升高10.98% (9/82),胃腸道反應(yīng) 12.20% (10/82)。4.在6-MP不良反應(yīng)中,白細(xì)胞減少、中性粒細(xì)胞減少、血紅蛋白下降、血小板減少及轉(zhuǎn)氨酶升高是常見(jiàn)的不良反應(yīng),其中白細(xì)胞及中性粒細(xì)胞減少以重度不良反應(yīng)為主,余均以輕度不良反應(yīng)為主。5. TPMT*3C基因型突變的2例患兒均出現(xiàn)嚴(yán)重不良反應(yīng),2例患兒均出現(xiàn)明顯的6-MP劑量不耐受,1/6標(biāo)準(zhǔn)劑量仍出現(xiàn)白細(xì)胞、中性粒細(xì)胞減少。[結(jié)論]1. 2例ALL患兒存在TPMT*3C基因突變。2. 6-MP維持治療期間最主要的近期不良反應(yīng)為骨髓抑制,主要導(dǎo)致白細(xì)胞、中性粒細(xì)胞減少,發(fā)生率分別是57.32%、59.76%。3. TPMT*3C基因突變的敏感性低,陽(yáng)性率低,不適合中國(guó)人群作為6-MP不良反應(yīng)的相關(guān)檢測(cè)基因,應(yīng)繼續(xù)尋找其他適合中國(guó)人群的巰嘌呤敏感基因。4.現(xiàn)研究發(fā)現(xiàn) TPMT* 2、TPMT* 3A、TPMT* 3B 和 TPMT* 3C 為最常見(jiàn)的基因突變類型,在本研究中僅發(fā)現(xiàn)TPMT*3C基因突變,此基因突變與6-MP不耐受密切相關(guān)。
[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.
【學(xué)位授予單位】：昆明醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R733.71

【參考文獻(xiàn)】

相關(guān)期刊論文 前7條

1 葉啟東;顧龍君;;兒童急性淋巴細(xì)胞白血病的個(gè)體化治療——TPMT和MTHFR基因多態(tài)性[J];中國(guó)實(shí)用兒科雜志;2016年04期

2 劉躍平;徐含青;楊翔;黃慶;府偉靈;;TPMT基因型在中國(guó)人群中的分布[J];臨床檢驗(yàn)雜志;2015年09期

3 李越;文飛球;;兒童白血病化療藥物基因組學(xué)研究進(jìn)展[J];中國(guó)實(shí)用兒科雜志;2015年06期

4 魏紅;黃民;李智毅;張禎;張建萍;吳玨珩;;中國(guó)哈薩克族人硫嘌呤甲基轉(zhuǎn)移酶活性分布和基因多態(tài)性[J];中國(guó)臨床藥理學(xué)雜志;2005年06期

5 王漢平,毛平,謝健晉,朱志剛;廣州地區(qū)人群中硫嘌呤甲基轉(zhuǎn)移酶基因的等位基因頻率及分布[J];臨床血液學(xué)雜志;2004年01期

6 張建萍,黃民,關(guān)永源,白麗,魏紅,吳玨珩;中國(guó)新疆維吾爾族硫嘌呤甲基轉(zhuǎn)移酶基因突變研究[J];中國(guó)臨床藥理學(xué)雜志;2003年05期

7 張建萍,關(guān)永源,吳玨珩,姜文奇,黃民;健康漢族人硫嘌呤甲基轉(zhuǎn)移酶遺傳多態(tài)性研究[J];癌癥;2003年04期

，

本文編號(hào)：1900051