摘要
目的:探讨NPM1基因突变阳性成人急性髓系白血病(NPM1+AML)患者的临床特征、伴随基因突变特征及影响预后的因素。方法:收集并应用第二代测序法测定22种AML常见的基因突变中NPM1基因突变阳性初诊成人AML患者73例,用实时荧光定量PCR法测定43种AML常见的融合基因,应用Kaplan-Meier生存曲线和Cox多因素回归分析影响预后的因素。结果:73例NPM1+AML患者中,共检测到74个NPM1基因位点突变,其发生率分别为L287fs(92.0%)、Q289fs和W288fs(2.7%)、L258fs和Q289H(1.4%),其中1例患者存在2个NPM1突变位点;不同突变位点对NPM1+AML的预后无影响。NPM1变异等位基因频率(VAF)的中位值为35.4(1.8-56.6)%,以四分位数上间距38.4%为界,NPM1 VAF>38.4%的AML患者(NPM1highAML)与NPM1VAF≤38.4%的患者(NPM1lowAML)相比,早期死亡率显著增加(33.3%vs 7.3%,P<0.05)、中位EFS(148 d,95%CI 58-238 vs 372 d,95%CI 264-480 d)(P<0.01)及中位OS(179 d,95%CI 6-352 d vs 444 d,P<0.01)均显著缩短。在87.7%的NPM1+AML患者中共检测到126个伴随基因突变;NPM1伴随NRAS基因突变的患者完全缓解率高(100%vs 58%)(P<0.05),且中位OS时间显著延长(未达到vs 320 d,95%CI 150-490 d)(P<0.05)。73例NPM1+AML患者中65例完善了43种融合基因检查,所有患者融合基因检查结果均为阴性。多因素分析显示,NPM1 VAF>38.4%是EFS(HR=3.1,95%CI 1.6-6.4,P<0.01)及OS(HR=3.0,95%CI 1.4-6.2,P<0.01)的独立预后不良因素。结论:AML患者NPM1基因突变常伴随其它基因突变,但罕有融合基因并存;NPM1高突变负荷是NPM1阳性成人AML患者的独立预后不良因素。
Objective:To investigate the clinical features,accompanying gene mutation characteristics and prognostic factors of adult patients with acute myeloid leukemia with mutated NPM1(NPM1^+ AML).Methods:Seventy-three patients with newly diagnosed adult NPM1^+ AML were selected.The mutations of 22 genes were detected by second generation sequencing and 43 fusion genes of AML were detected by real-time fluorescent quantitative PCR.The KaplanMeier survival curve and Cox multivariate regression analysis were used to study the prognostic factors.Results:A total of 74 NPM1 site mutations were detected in 73 patients with NPM1^+ AML.The incidence rates were 92.0% L287 fs,2.7%Q289 fs and W288 fs,1.4% L258 fs and Q289 H,among which 1 patient had 2 NPM1 mutations;the different mutation sites had no effect on the prognosis of NPM1+AML.The median value of NPM1 variant allele frequency(VAF)was35.4%(1.8%-56.6%).Based on the uppermost quartile of 38.4%,the patients were classified as NPM1 VAF>38.4%(NPM1^high AML)and NPM1 VAF≤38.4%(NPM1^low AML).Compared with NPM1^low AML,the early mortality rate was statistically significantly higher(33.3% vs 7.3%,P<0.05),and median EFS(148 d,95%CI 58-238 d vs 372 d,95%CI264-480 d)(P<0.01)and median OS(179 d 95%CI 6-352 d vs 444 d)(P<0.01)were significantly shorter in NPM1^high AML.A total of 126 accompanying gene mutation sites were detected in 87.7% of patients with NPM1^+ AML.The patients with NRAS gene mutation displayed a higher rate of complete remission(100% vs 58%)(P<0.05)and longer median OS(not reached to 320 d,95%CI 150-490 d)(P<0.05).The 43 fusion genes were examined in 65 out of 73 cases of NPM1^+ AML,and in all the patients the fusion gene test was negative.Multivariate analysis showed that NPM1 VAF>38.4% was an independent prognostic factor for EFS(HR=3.1,95% CI 1.6-6.4,P<0.01)and OS(HR=3.0,95% CI 1.4-6.2,P<0.01).Conclusion:The NPM1 gene mutation in AML patients often is accompanied by other gene mutations,while the coexistence of fusion genes is rare;high NPM1 mutant allele burden i
作者
侯降雪
王树娟
刘延方
郝倩倩
王冲
李涛
白俊俊
廖林晓
郭程娱
常银银
王萌
孙慧
谢新生
姜中兴
HOU Jiang-Xue;WANG Shu-Juan;LIU Yan-Fang;HAO Qian-Qian;WANG Chong;LI Tao;BAI Jun-Jun;LIAO Lin-Xiao;GUO Cheng-Yu;CHANG Yin-Yin;WANG Meng;SUN Hui;XIE Xin-Sheng;JIANG Zhong-Xing(Department of Hematology,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,Henan Province,China;Shanghai Yuan Qi Biological Medicine Technology Co.,Ltd,Shanghai 201400,China)
出处
《中国实验血液学杂志》
CAS
CSCD
北大核心
2019年第2期365-372,共8页
Journal of Experimental Hematology
基金
国家自然科学基金项目(U1504806
81800137)
