老年急性髓系白血病基因突变及临床意义

连芸; 黄佳瑜; 张晶晶; 李珊; 赵慧慧; 乔纯; 洪鸣; 朱雨; 李建勇; 钱思轩

doi:10.13201/j.issn.1004-2806.2018.01.004

老年急性髓系白血病基因突变及临床意义

- 南京医科大学第一附属医院, 江苏省人民医院血液科, 南京医科大学血液研究重点实验室(南京, 210029)
基金项目:
国家自然科学基金资助项目(No:81570134)

详细信息

通讯作者: 钱思轩,E-mail:qiansx@medmail.com.cn

中图分类号: R733.71

收稿日期: 2017-09-12

Mutation and its clinical significance of acute myeloid leukemia in elderly patients

- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China

More Information

Corresponding author: QIAN Sixuan, E-mail: qiansx@medmail.com.cn

Received Date: 12 September 2017

摘要

摘要: 目的:探讨老年急性髓系白血病(AML)患者基因突变情况及其临床意义。方法:采用二代测序方法检测69例初诊老年AML患者基因突变情况,包括TET2,DNMT3A,NPM1,CEBPα,EZH2,JAK2,U2AF1,RUNX1,NRAS,TP53,IDH2,C-KIT,SRSF2,SF3B1,ASXL1,FLT3,ETV6,PHF6,CBL,SETBP1,ZRSR2,收集患者临床资料,分析突变发生率及临床意义,针对49例接受DCAG治疗患者分析疗效及预后。结果:老年AML患者基因突变频率高,突变率为94.2%(65/69),NPM1,SRSF2,SF3B1在4种白血病分型间分布存在差异(均P<0.05)。C-KIT突变易出现在染色体核型低中危组(P<0.001),TP53突变与高危核型有关(P=0.003)。TP53突变,ETV6突变,合并症数目,染色体核型及DCAG首次诱导完全缓解均为影响预后的因素,其中TP53突变,首次诱导完全缓解及合并症数目为独立危险因素(P<0.05)。结论:老年AML患者基因突变及细胞遗传学异常对临床诊疗工作具有重要意义。
- 基因突变 /
- 急性髓系白血病 /
- 二代测序
Abstract: Objective:To investigate the mutations and clinical significance of genes in elderly patients with acute myeloid leukemia (AML).Method:Next-generation sequencing was used to detect newly diagnosed elderly AML patients,including TET2,DNMT3A,NPM1,CEBPα,EZH2,JAK2,U2AF1,RUNX1,NRAS,TP53,IDH2,C-KIT,SRSF2,SF3B1,ASXL1,FLT3,ETV6,PHF6,CBL,SETBP1,ZRSR2.We collected the clinical data and analyzed the incidence as well as clinical significance.The efficacy and prognosis of 49 patients treated with DCAG were analyzed.Result:The prevalence of the selected mutations was 94.2%(65/69) in elderly patients with AML,and the distribution of NPM1,SRSF2 and SF3B1 were different among 4 leukemia types (P<0.05).C-KIT mutations were found in the group with low-risk chromosome karyotype (P<0.001) and TP53 mutations were associated with poor-risk group chromosome karyotype (P=0.003).TP53 mutation,ETV6 mutation,the number of complications,chromosome karyotype and achievement of complete remission after DCAG first induction were the prognostic factors,whereas TP53 mutation,achievement of complete remission after the first induction and complications were independent risk factors (P<0.05).Conclusion:Gene mutation and cytogenetic abnormalities in elderly patients with AML have great significance to clinical diagnosis and treatment.
- gene mutation /
- acute myeloid leukemia /
- next-generation sequencing

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参考文献(28)

[1]	Sanford D, Ravandi F.Management of newly diagnosed acute myeloid leukemia in the elderly:Current strategies and future directions[J].Drugs Aging, 2015, 32:983-997.
[2]	Tsai CH, Hou HA, Tang JL, et al.Genetic alterations and their clinical implications in older patients with acute myeloid leukemia[J].Leukemia, 2016, 30:1485-1492.
[3]	Klco JM, Miller CA, Griffith M, et al.Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia[J].JAMA, 2015, 314:811-822.
[4]	Metzeler KH, Herold T, Rothenberg-Thurley M, et al.Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia[J].Blood, 2016, 128:686-698.
[5]	Bullinger L, Dohner K, Dohner H.Genomics of acute myeloid leukemia diagnosis and pathways[J].J Clin Oncol, 2017, 35:934-946.
[6]	Su L, Li X, Gao S-J, et al.Cytogenetic and genetic mutation features of de novo acute myeloid leukemia in elderly Chinese patients[J].Asian Pac J Cancer Prev, 2014, 15:895-898.
[7]	Lin PH, Li HY, Fan SC, et al.A targeted next-generation sequencing in the molecular risk stratification of adult acute myeloid leukemia:Implications for clinical practice[J].Cancer Med, 2017, 6:349-360.
[8]	Li J, Chen Y, Zhu Y, et al.Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia[J].Oncotarget, 2015, 6:6448-6458.
[9]	Genovese G, Kahler AK, Handsaker RE, et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence[J].N Engl J Med, 2014, 371:2477-2487.
[10]	Mian SA, Rouault-Pierre K, Smith AE, et al.SF3B1mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment[J].Nat Commun, 2015, 6:10004.
[11]	Dolatshad H, Pellagatti A, Fernandez-Mercado M, et al.Disruption of SF3B1results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells[J].Leukemia, 2015, 29:1092-1103.
[12]	Lindsley RC, Mar BG, Mazzola E, et al.Acute myeloid leukemia ontogeny is defined by distinct somatic mutations[J].Blood, 2015, 125:1367-1376.
[13]	Hou HA, Liu CY, Kuo YY, et al.Splicing factor mutations predict poor prognosis in patients with de novo acute myeloid leukemia[J].Oncotarget, 2016, 7:9084-9101.
[14]	Papaemmanuil E, Gerstung M, Bullinger L, et al.Genomic classification and prognosis in acute myeloid leukemia[J].N Engl J Med, 2016, 374:2209-2221.
[15]	Wong TN, Ramsingh G, Young AL, et al.Role of TP53mutations in the origin and evolution of therapyrelated acute myeloid leukaemia[J].Nature, 2015, 518:552-555.
[16]	Ohgami RS, Ma L, Merker JD, et al.Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2mutations[J].Mod Pathol, 2015, 28:706-714.
[17]	Rücker FG, Schlenk RF, Bullinger L, et al.TP53alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome[J].Blood, 2012, 119:2114-2121.
[18]	Welch JS, Petti AA, Miller CA, et al.TP53and decitabine in acute myeloid leukemia and myelodysplastic syndromes[J].N Engl J Med, 2016, 375:2023-2036.
[19]	Marcucci G, Haferlach T, Dohner H.Molecular genetics of adult acute myeloid leukemia:prognostic and therapeutic implications[J].J Clin Oncol, 2011, 29:475-486.
[20]	CG M.The molecular genetic makeup of acute lymphoblastic leukemia[J].Hematology Am Soc Hematol Educ Program, 2012, 2012:389-396.
[21]	Bejar R, Stevenson K, Abdel-Wahab O, et al.Clinical effect of point mutations in myelodysplastic syndromes[J].N Engl J Med, 2011, 364:2496-2506.
[22]	Nibourel O, Kosmider O, Cheok M, et al.Incidence and prognostic value of TET2alterations in de novo acute myeloid leukemia achieving complete remission[J].Blood, 2010, 116:1132-1135.
[23]	Ahn JS, Kim HJ, Kim YK, et al.5-hydroxymethylcytosine correlates with epigenetic regulatory mutations, but may not have prognostic value in predicting survival in normal karyotype acute myeloid leukemia[J].Oncotarget, 2017, 8:8305-8314.
[24]	Liu WJ, Tan XH, Luo XP, et al.Prognostic significance of Tet methylcytosine dioxygenase 2 (TET2) gene mutations in adult patients with acute myeloid leukemia:a meta-analysis[J].Leuk Lymphoma, 2014, 55:2691-2698.
[25]	Bejar R, Lord A, Stevenson K, et al.TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients[J].Blood, 2014, 124:2705-2712.
[26]	Patel JP, G9nen M, Figueroa ME, et al.Prognostic relevance of integrated genetic profiling in acute myeloid leukemia[J].N Engl J Med, 2012, 366:1079-1089.
[27]	Ostronoff F, Othus M, Lazenby M, et al.Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia:A SWOG and UK National Cancer Research Institute/Medical Research Council report[J].J Clin Oncol, 2015, 33:1157-1164.
[28]	Kihara R, Nagata Y, Kiyoi H, et al.Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients[J].Leukemia, 2014, 28:1586-1595.