非髓性白血病的其他恶性血液病中DNMT3A基因突变的检测及临床意义
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摘要
目的:了解DNMT3A基因突变在非髓性白血病的其他恶性血液肿瘤患者中的发生率、分布情况及临床意义。方法:选取196例非髓性白血病的其他血液肿瘤患者为研究对象,提取患者外周血基因组DNA,针对DNMT3A基因突变热点R882位点设计引物,采用聚合酶链式反应(PCR)法扩增DNMT3A基因23号外显子整个编码区基因片段,再将扩增产物纯化后测序,分析DNMT3A基因突变在本组恶性血液病患者中的发生率、分布情况及临床意义。结果:在57例非霍奇金淋巴瘤及34例骨髓增生异常综合征患者中各检出1例伴DNMT3A基因突变,在25例急性淋巴细胞白血病、45例多发性骨髓瘤和35例骨髓增殖性肿瘤患者中均未检测到DNMT3A基因突变。结论:非髓性白血病的其他血液肿瘤患者中DNMT3A基因突变少见,伴DNMT3A基因突变的1例T淋巴母细胞白血病/淋巴瘤患者预后不良,联合去甲基化药物的化疗方案使伴该基因突变的1例骨髓增生异常综合征患者一度获得血液学完全缓解,但短期内转为急性白血病并发严重感染死亡。
Objective: To evaluate the rate of DNMT3 A gene mutation in hematologic malignancies except for myeloid leukemia and evaluate its clinical value. Methods: Genomic DNA samples were extracted from 196 patients with hematologic malignancy. Polymerase Chain Reaction( RCR) was used to amplify the 23 rd exon covering R882 codon,the mutational hotspot of DNMT3 A gene. Then,sanger sequencing was performed to detect gene mutations of the purified DNA fragments. Results: One case with DNMT3 A gene mutation was identified in 57 patients with non-Hodgkin lymphoma and in 34 patients with myelodysplastic syndrome( MDS),respectively. However,DNMT3 A gene mutation was not detected in 25 patients with acute lymphoblastic leukemia,45 patients with multiple myeloma and 35 patients with myeloproliferative neoplasm. Conclusion: DNMT3 A gene mutation is a rare event in hematologic malignancies except for myeloid leukemia. In our study,DNMT3 A gene mutation was identified only in two patients,one case with T lymphoblastic leukemia/lymphoma had a poor prognosis,the other diagnosed as MDS achieved completely hematologic remission after treatment with decitabine and chemotherapy,but soon progressed to acute leukemia.
Objective: To evaluate the rate of DNMT3 A gene mutation in hematologic malignancies except for myeloid leukemia and evaluate its clinical value. Methods: Genomic DNA samples were extracted from 196 patients with hematologic malignancy. Polymerase Chain Reaction( RCR) was used to amplify the 23 rd exon covering R882 codon,the mutational hotspot of DNMT3 A gene. Then,sanger sequencing was performed to detect gene mutations of the purified DNA fragments. Results: One case with DNMT3 A gene mutation was identified in 57 patients with non-Hodgkin lymphoma and in 34 patients with myelodysplastic syndrome( MDS),respectively. However,DNMT3 A gene mutation was not detected in 25 patients with acute lymphoblastic leukemia,45 patients with multiple myeloma and 35 patients with myeloproliferative neoplasm. Conclusion: DNMT3 A gene mutation is a rare event in hematologic malignancies except for myeloid leukemia. In our study,DNMT3 A gene mutation was identified only in two patients,one case with T lymphoblastic leukemia/lymphoma had a poor prognosis,the other diagnosed as MDS achieved completely hematologic remission after treatment with decitabine and chemotherapy,but soon progressed to acute leukemia.
引文
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[10]Coombs CC,Sallman DA,Devlin SM,et al.Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia[J].Haematologica,2016,101(11):e457-e460.
[11]Stegelmann F,Bullinger L,Schlenk RF,et al.DNMT3A mutations in myeloproliferative neoplasms[J].Leukemia,2011,25(7):1217-1219.
[12]Kim MS,Kim YR,Yoo NJ,et al.Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers[J].Apmis,2013,121(2):85-94.
[13]Yanan Liu,Na Zhang,Ying Wu,et al.DNMT3A mutation analysis in adult patients with acute lymphoblastic leukemia[J].J Huazhong Univ Sci Technol(Med Sci),2015,35(3):337-342.
[14]Li W,Gao C,Cui L,et al.DNMT3A mutations and prognostic significance in childhood acute lymphoblastic leukemia[J].Leuk Lymphoma,2015,56(4):1066-1071.(编校:刘跳英)
[2]Swerdlow SH,Campo E,Pileri SA,et al.The 2016 revision of the world health organization classification of lymphoid neoplasms[J].Blood,2016,127(20):2375-2390.
[3]Arber DA,Orazi A,Hasserjian R,et al.The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia[J].Blood,2016,127(20):2391-2405.
[4]Lou Dian,Zhou Xinfu,Luo Zimian,et al.Detection of DNMT3a mutation in acute myelogenous leukemia and its clinical significance[J],Chinese J Hematology,2014,35(2):165-167.[娄典,周新伏,罗自勉,等.急性髓系白血病患者DNMT3A基因突变分析[J].中华血液学杂志,2014,35(2):165-167.]
[5]CouronnéL,Bastard C,Bernard OA.TET2 and DNMT3A mutations in human T-cell lymphoma[J].N Engl J Med,2012,366(1):95-96.
[6]Walter MJ,Ding L,Shen D,et al.Recurrent DNMT3A mutations in patients with myelodysplastic syndromes[J].Leukemia,2011,25(7):153-1158.
[7]Thol F,Winschel C,Ludeking A,et al.Rare occurrence of DNMT3A mutations in myelodysplastic syndromes[J].Hematologica,2011,96(12):1870-1873.
[8]Lin J,Yao DM,Qian J,et al.Recurrent DNMT3A R882mutations in chinese patients with acute myeloid leukemia and myelodysplastic syndrome[J].Plos one,2011,6(10):26906.
[9]Xu Jing,Li Guoxia,Chang Jianmei,et al.Analysis of molecular and cytogenetic features in 42 patients with myelodysplastic syndromes[J].Chin J Clinicians(Electronic Edition),2016,10(22):3348-3351.[许晶,李国霞,常建梅,等.骨髓增生异常综合征患者42例分子及细胞遗传学特征分析[J].中华临床医师杂志(电子版),2016,10(22):3348-3351.]
[10]Coombs CC,Sallman DA,Devlin SM,et al.Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia[J].Haematologica,2016,101(11):e457-e460.
[11]Stegelmann F,Bullinger L,Schlenk RF,et al.DNMT3A mutations in myeloproliferative neoplasms[J].Leukemia,2011,25(7):1217-1219.
[12]Kim MS,Kim YR,Yoo NJ,et al.Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers[J].Apmis,2013,121(2):85-94.
[13]Yanan Liu,Na Zhang,Ying Wu,et al.DNMT3A mutation analysis in adult patients with acute lymphoblastic leukemia[J].J Huazhong Univ Sci Technol(Med Sci),2015,35(3):337-342.
[14]Li W,Gao C,Cui L,et al.DNMT3A mutations and prognostic significance in childhood acute lymphoblastic leukemia[J].Leuk Lymphoma,2015,56(4):1066-1071.(编校:刘跳英)