伴NPM1突变急性髓系白血病二代测序突变基因谱与MICM分型特征关联性分析  

Association of Next Generation Sequencing Based Genotypic Profiling with MICM Characteristics in NPM1 Mutated Acute Myeloid Leukemia

作　　者：王彪[1] 凌云[1] 戴莉[1] 顾伟英[1] 张修文 邢珊珊 李海乾[1] WANG Biao;LING Yun;DAI Li;GU Wei-Ying;ZHANG Xiu-Wen;XING Shan-Shan;LI Hai-Qian(Department of Hematology,The Third Affiliated Hospital of Soochow University(The First People's Hospital of Changzhou),Changzhou 213003,Jiangsu Province,China;Department of Hematology,Nanjing Medical University Affiliated Changzhou Second Hospital,Changzhou 213164,Jiangsu Province,China;Department of Hematology,Zhejiang Hospital,Hangzhou 310013,Zhejiang Province,China)

机构地区：[1]苏州大学附属第三医院(常州市第一人民医院)血液科,江苏常州213003 [2]南京医科大学附属常州第二人民医院血液科,江苏常州213164 [3]浙江医院血液科,浙江杭州310013

出　　处：《中国实验血液学杂志》2022年第1期56-64,共9页Journal of Experimental Hematology

摘　　要：目的:分析伴NPM1突变(NPM1^(mut))急性髓系白血病(AML)患者二代测序(NGS)法检测的突变基因谱与MICM特征间的关系,解释NPM1^(mut)AML的临床生物学异质性。方法:收集苏州大学附属第三医院、南京医科大学附属常州第二人民医院和浙江医院收治的成人初诊AML患者,选取NGS资料完整的NPM1^(mut)患者238例,采用χ^(2)检验和非参数检验分析NGS突变基因谱与常规MICM参数间的分布关联性。结果:全部患者共检出240个NPM1突变事件,其中10个(10/240,4.2%)为错义突变,均不累及W288或W290位点。这10例错义突变事件仅见于NPM1^(mut)/FLT3-ITD^(-)者,其中9例(90%)同时合并AML亚型定义的细胞遗传学或分子学异常,且全部为低危(7例)或高危(2例)组。NPM1^(mut)/FLT3-ITD^(+)者NPM1^(mut)仅为插入/缺失(indel)突变。NPM1^(mut)/FLT3-ITD^(-)者高危+低危组异常核型发生率显著高于NPM1^(mut)/FLT3-ITD^(+)者(6.4%vs.0,P=0.031)。NPM1^(mut)/FLT3-ITD^(+)者CD34和CD7阳性率均显著高于NPM1^(mut)/FLT3-ITD^(-)者(CD34:47.9%vs.20.6%,P<0.001;CD7:61.5%vs.29.9%,P<0.001)。Logistic多因素分析显示,FLT3-ITD独立预测CD34^(+)(OR=5.29,95%CI:2.64-10.60,P<0.001)和CD7^(+)(OR=3.47,95%CI:1.79-6.73,P<0.001)。Ras通路突变独立预测HLA-DR^(+)(OR=4.05,95%CI:1.70-9.63,P=0.002),KRAS突变独立预测MPO^(-)(OR=0.18,95%CI:0.05-0.62,P=0.007)。TET2/IDH1突变独立预测CD34^(-)(OR=0.26,95%CI:0.11-0.62,P=0.002)、CD7^(-)(OR=0.30,95%CI:0.14-0.62,P=0.001)和MPO^(+)(OR=3.52,95%CI:1.48-8.38,P=0.004)。DNMT3A-R882独立预测HLA-DR^(+)(OR=13.41,95%CI:4.56-39.45,P<0.001)和CD7^(+)(OR=3.59,95%CI:1.80-7.16,P<0.001),DNMT3A突变独立预测MPO^(-)(OR=0.35,95%CI:1.48-8.38,P=0.004)。结论:NPM1^(mut)AML共存FLT3-ITD预测CD34^(+)和CD7^(+),共存Ras通路突变预测HLA-DR^(+)和MPO^(-),共存TET2/IDH1突变预测CD34^(-)、CD7^(-)和MPO^(+),共存DNMT3A突变预测HLA-DR^(+)、CD7^(+)和MPO^(-),这为患者免疫表型异质性提供了部分机制解释。Objective:To explain the clinicobiological heterogeneity of NPM1 mutated(NPM1^(mut))acute myeloid leukemia(AML)by analyzing the association between next-generation sequencing(NGS)profiles and MICM characteristics in patients with this AML subtype.Methods:Data of 238 NPM1^(mut) patients with available NGS information on 112 genes related to blood disease was collected,andχ^(2) test and nonparametric test were used to analyze the distribution association between NGS-detecting mutations and conventional MICM parameters.Results:In entire NPM1^(mut) cohort,totaling 240 NPM1 mutation events were identified,of whom 10(10/240,4.2%)were missense mutations,which did not involve any W288 or W290 locus and were found exclusively in NPM1^(mut)/FLT3-ITD-group.All but one of these missense mutations(9/10,90%)were accompanied by AML subtype-defining recurrent cytogenetic or molecular abnormalities,of which 7 cases were in the low risk and 2 in the high risk.NPM1^(mut) occurred solely as an insertion/deletion(indel)type in the NPM1^(mut)/FLT3-ITD^(+) group.The incidence of favorable plus unfavorable karyotypes in NPM1^(mut)/FLT3-ITD^(-) group was higher than in NPM1^(mut)/FLT3-ITD^(+) group(6.4%vs.0,P=0.031).The positive rates of CD34 and CD7 in NPM1^(mut)/FLT3-ITD^(+) group were significantly higher than in NPM1^(mut)/FLT3-ITD^(-) group(CD34:47.9%vs.20.6%,P<0.001;CD7:61.5%vs.29.9%,P<0.001).Logistic analysis showed that FLT3-ITD independently predicted for CD34^(+) and CD7^(+)[odds ratio(OR)=5.29,95%CI:2.64-10.60,P<0.001;OR=3.47,95%CI:1.79-6.73,P<0.001;respectively].Ras-pathway mutations independently predicted for HLA-DR^(+)(OR=4.05,95%CI:1.70-9.63,P=0.002),and KRAS mutation for MPO^(-)(OR=0.18,95%CI:0.05-0.62,P=0.007).TET2/IDH1 mutations independently predicted for CD34^(-)and CD7^(-)(OR=0.26,95%CI:0.11-0.62,P=0.002;OR=0.30,95%CI:0.14-0.62,P=0.001;respectively),and MPO^(+)(OR=3.52,95%CI:1.48-8.38,P=0.004).DNMT3 A-RS882 independently predicted for CD7^(+)and HLA-DR^(+)(OR=3.59,95%CI:1.80-7.16,P<0.001;OR=13.41,95%CI:4.56-39.45,P

关 键 词：NPM1 FLT3-ITD 急性髓系白血病 免疫表型 二代测序 

分 类 号：R733.71[医药卫生—肿瘤]