NPM1突变急性髓系白血病二代测序突变基因谱及共存互斥相关性分析  

The Mutated Gene Sequenced by NGS and the Correlation of Their Coexistent Mutual Exclusiveness in NPM1 Mutated Acute Myeloid Leukemia

作　　者：戴莉[1] 王志林[1] 邱国强[1] 吴义存 张修文 邢珊珊 王彪[1] DAI Li;WANG Zhi-Lin;QIU Quo-Qiang;WU Yi-Cun;ZHANG Xiu-Wen;XING Shan-Shan;WANG Biao(Department of Hematology,The Third Affiliated Hospital of Soochovv University(Changzhou First People's Hospital),Changzhou 213000,Jiangsu Province,China;Department of Hematology,Nanjing Medical University Affiliated Changzhou Second Hospital,Changzhou 213000,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213000 [2]南京医科大学附属常州第二人民医院血液科,江苏常州213000 [3]浙江医院血液科,杭州310013

出　　处：《中国实验血液学杂志》2021年第6期1733-1740,共8页Journal of Experimental Hematology

摘　　要：目的:分析NPM1突变(NPM1^(mut))急性髓系白血病(AML)患者二代测序(NGS)检测的突变基因谱及其共存互斥关系,以解释NPM1^(mut)AML的临床生物学异质性。方法:收集238例成人初诊NPM1^(mut)患者基于112种血液病相关基因的NGS资料,采用χ^(2)检验和非参数检验分析突变谱基因间分布相关性。结果:全部NPM1^(mut)患者均检出至少1个共存突变。包括NPM1^(mut),中位数突变基因个数/每例为4.5 (2-14)个。其中NPM1^(mut)/FLT3-ITD;者突变基因个数为5.0 (2-10)个,多于NPM1^(mut)/FLT3-ITD;者[4.0(2-14)个],但两者间无统计学差异(P=0.378)。全部238例NPM1^(mut)患者共检出240例NPM1突变事件,其中10个(10/240,4.2%)为错义突变,且均见于NPM1^(mut)/FLT3-ITD;者。这些错义突变绝大多数(9/10,90%)同时合并AML亚型定义的细胞遗传学或分子学异常,且均为低危(7例)或高危组(2例)。分析相对常见(突变率>5%)的NPM1^(mut)共存突变基因谱,最常见的为DNMT3A(104例,43.7%),其次为FLT3-ITD(95例,39.9%)和FAT1(57例,23.9%)。FLT3-ITD与DNMT3A间呈显著性突变共存(P=0.005)。FLT3-ITD与FLT3-nonITD(P<0.001)、NRAS(P<0.001)、PTPN11(P=0.017)以及IDH1(P=0.005)间呈显著性突变排斥,与KRAS间呈临界意义突变排斥倾向(P=0.073)。FLT3-nonITD与KRAS间(P=0.035)、NRAS与KRAS(P=0.008)和PTPN11(P=0.039)间显著性突变共存。结论:阐述NPM1^(mut)患者的临床预后时,应区别对待相对少见的错义突变类型。检测NPM1^(mut)AML突变基因谱全貌和了解突变间共存关系,为患者生物学多样性和临床异质性提供了机制解释。Objective: To analyze the clinicobiological heterogeneity of NPM1^(mut)ated( NPM1^(mut)) acute myeloid leukemia( AML) detected by next generation sequencing( NGS) and their coexistence and mutual exclusivity relationship in the AML subtype. Methods: The NGS data based on 112 genes related to blood disease in 238 newly diagnosed patients with NPM1^(mut)were collected. The χ2 test and non-parametric test were used to analyze the distribution correlation between the genes in the mutational spectrum. Results: Among all the patients,at least one co-mutation was detected out. The median number per case of the mutated genes,including NPM1^(mut)was 4.5( range 2-14),among them,there were 5.0( range 2-10) for NPM1^(mut)/FLT3-ITD;and 4.0( range 2-14) for NPM1^(mut)/FLT3-ITD-cases,but it was no significant difference between the two groups( P = 0. 378). A total of 240 NPM1^(mut)ational events were detected out in entire 238 NPM1^(mut)patients,of which 10( 4. 2%) were missense mutations,and were all found in NPM1^(mut)/FLT3-ITD-patients. Most( 9/10,90%) of these NPM1 missense mutations were accompanied by AMLsubtype-defining cytogenetic or molecular abnormalities,of which 7 patients were in low risk or 2 in high risk. The most common NPM1^(mut)coexisting mutations were DNMT3 A( 104,43. 7%),followed were FLT3-ITD( 95,39. 9%) and FAT1( 57,23. 9%),FLT3-ITD and DNMT3 A showed significant coexistence( P = 0. 005). FLT3-ITD showed significantly reciprocal exclusivity with FLT3-nonITD( P<0.001),NRAS( P<0.001),PTPN11( P = 0.017) and IDH1( P= 0.005),and showed an exclusivity inclination with KRAS( P= 0.073). In addition,FLT3-nonITD along with KRAS( P= 0. 035),NRAS along with KRAS( P = 0. 008) and PTPN11( P = 0. 039) coexisted significantly. Conclusion:Prognoses of AML involving less common NPM1 missense mutations should be stated on a case by case basis. The mutational landscape and co-occurrence and mutual exclusivity correlations of NPM1^(mut)AML provide a mechanism explaining biological diversity and clinical heterogeneity in this

关 键 词：NPM1 FLT3-ITD 急性髓系白血病 二代测序 突变 

分 类 号：K733.71[历史地理—历史学]