文章摘要
刘 洁,华海应,晁红颖,蔡晓辉,张修文,陈梅玉,卢绪章,刘建芳.急性髓系白血病中DNMT3A p.R882的共存基因突变分析[J].南京医科大学学报,2020,(9):1331~1337
急性髓系白血病中DNMT3A p.R882的共存基因突变分析
Mutation analysis of coexisting genes with DNMT3A p.R882 in acute myeloid leukemia
投稿时间:2019-08-12  
DOI:10.7655/NYDXBNS20200915
中文关键词: 急性髓系白血病  突变  DNMT3A  NPM1
英文关键词: acute myeloid leukemia  mutation  DNMT3A  NPM1
基金项目:国家自然科学基金青年基金(81500103);江苏省自然科学基金青年基金(BK20160283);常州市科技计划资助(CJ20180033);常州市应用基础研究(CJ20140060)
作者单位
刘 洁 南京医科大学附属常州市第二人民医院血液科江苏 常州 213003 
华海应 无锡市第三人民医院血液科江苏 无锡 214041 
晁红颖 南京医科大学附属常州市第二人民医院血液科江苏 常州 213003 
蔡晓辉 南京医科大学附属常州市第二人民医院血液科江苏 常州 213003 
张修文 南京医科大学附属常州市第二人民医院血液科江苏 常州 213003 
陈梅玉 南京医科大学附属常州市第二人民医院血液科江苏 常州 213003 
卢绪章 南京医科大学附属常州市第二人民医院血液科江苏 常州 213003 
刘建芳 南京医科大学附属常州市第二人民医院神经内科江苏 常州 213003 
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中文摘要:
      目的:探讨急性髓系白血病(acute myeloid leukemia,AML)患者中DNA甲基转移酶3A(DNA methyltransferase 3A,DNMT3A)p.R882的共存基因突变及其与部分临床参数间的相关性。方法:采用高通量DNA测序技术检测49种靶基因;采用基因组DNA?PCR联合Sanger测序法检测患者中DNMT3A p.R882、CALR基因9号外显子、NPM1基因12号外显子、FLT3?ITD,及CEBPA的TAD、BZIP两个功能结构域的突变发生情况。结果:① 301例患者中共检出41例携带DNMT3A p.R882突变,最常见为M5亚型;97.6%(40/41)DNMT3A p.R882突变患者同时携带其他基因突变,每例患者平均突变3.17次;其中双基因突变9例,3个基因突变共存12例,≥4个基因突变共存19例。② DNMT3A p.R882伴随基因突变最常见的为NPM1(n=27,65.9%),其他依次为:FLT3?ITD(n=18,43.9%)、IDH1(n=9,22.0%)、TET2(n=8,19.5%)及NRAS(n=6,14.6%)等;③ ≥4个基因突变患者的白细胞水平虽然高于双基因及3个基因突变者,但差异无统计学意义(P>0.05),同样血红蛋白及血小板水平差异亦无统计学意义(P>0.05),共存基因突变为FLT3?ITD者的外周白细胞水平高于野生型(P=0.034),但在年龄、血红蛋白及血小板水平方面的差异无统计学意义。伴NPM1、IDH1或TET2突变者与野生型相比,在中位年龄、外周血白细胞水平间的差异均无统计学意义。④ 与野生型相比,伴NPM1突变者具有更高的初次诱导完全缓解(complete remission,CR)率,而伴IDH1突变者CR率较低,差异均有统计学意义(P=0.010,0.025);伴FLT3?ITD与TET2突变者与野生型相比,在CR率方面的差异无统计学意义。结论:95%以上的DNMT3A p.R882突变AML均伴有额外基因突变,共存基因突变种类及个数对患者的临床特征有一定影响。
英文摘要:
      Objective:This study aims to investigate the coexisting mutation of DNA methyltransferase 3A(DNMT3A)p.R882 in patients with acute myeloid leukemia(AML)and its correlation with some clinical parameters. Methods:There were 49 target genes detected by high?throughput DNA sequencing,and the mutations of DNMT3A p.R882,exon 9 of CALR gene,exon 12 of NPM1 gene,FLT3?ITD,TAD and BZIP of CEBPA were detected by genomic DNA?PCR combined with Sanger sequencing. Results:①Forty?one patients with DNMT3A p.R882 mutations were detected in 301 patients,most common in M5 subtype;nearly all DNMT3A p.R882 mutations(97.6%,40/41)carried other gene mutations,with an average of 3.17 mutations per patient,including 9 double gene mutations,12 co?existing 3 gene mutations and 19 coexisting ≥ 4 gene mutations. ②The most common genetic mutation associated with DNMT3Ap.R882 is NPM1(n=27,65.9%),followed by FLT3?ITD(n=18,43.9%),IDH1(n=9,22.0%),TET2(n=8,19.5%)and NRAS(n=6,14.6%),and so on. ③The leukocyte level of patients with ≥ 4 gene mutations was higher than that of patients with double or three gene mutations,but there was no significant difference in leukocyte,hemoglobin or platelet level(P>0.05). The peripheral leukocyte level of patients with FLT3?ITD gene mutations was higher than that of wild patients(P=0.034),but there was no significant difference in age,hemoglobin and platelet level. And there was no significant difference in median age and peripheral leukocyte level between NPM1,IDH1 or TET2 mutants and wild type. ④Compared with the wild type,patients with NPM1 mutations had a higher complete remission(CR)rate,while the patients with IDH1 mutations had a lower CR rate(P=0.010,0.025). But there was no significant difference in CR rate between the patients with FLT3?ITD on TET2 mutations and the wild type. Conclusion:More than 95% of DNMT3A p.R882?mutated AML coexisted with additional gene mutations,the number and type of coexisting mutations had a certain impact on the clinical characteristics of patients.
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