不同基因突变对于急性髓系白血病预后的影响

Effects of different gene mutations on the prognosis of acute myeloid leukemia

目的:探究急性髓系白血病(AML)患者基因突变谱及其与预后的关系。方法:回顾性收集2018年1月至2021年12月初诊于中山大学附属第三医院血液内科的AML患者的临床资料,进行靶向深度测序(NGS 175-Panel)检测患者基因突变,绘制基因突变谱,分析基因突变间的共存与互斥关系以及与临床特征之间的关系;使用Kaplan-Meier生存曲线和Cox风险比例模型进行基因突变相关的预后分析,包括总生存期(OS)与无事件生存期(EFS)。结果:140例初诊AML病例共发生了433个突变,FLT3、CEBPA、NPM1、WT1、IDH2是突变频率最高的5个基因,而本研究中WT1、CEBPA、NPM1、DNMT3A等基因的突变频率显著高于西方人群,同时发现了22对基因共存与互斥关系以及不同基因突变与临床特征的相关性(均P<0.05)。此外,生存分析显示,FLT3-ITD(OS:P=0.047,EFS:P=0.097),NRAS(OS:P=0.003,EFS:P=0.300)和WT1(OS:P=0.110,EFS:P=0.004)与较差的OS或EFS相关,FLT3-ITD阳性伴WT1突变患者的OS与EFS显著差于双阴性或单一阳性的AML患者(OS:P<0.001,EFS P=0.005)。同时FLT3-ITD插入位置与临床特征以及预后的相关性分析显示,当FLT3-ITD插入位置仅发生在近膜结构域(JMDsole)时,OS显著差于插入位置发生在近膜结构域与酪氨酸结构域之间(JMD/TKD1)(P=0.007)。结论:不同人群的AML基因突变谱存在显著差异,NRAS和WT1基因突变以及FLT3-ITD和WT1共突变提示预后不良。

Objective:To investigate the gene mutation landscape and its relationship with prognosis in acute myeloid leukemia(AML)patients.Methods:Retrospective analysis of clinical data from AML patients newly diagnosed between January 2018 and December 2021 in the Department of Hematology,the Third Affiliated Hospital of Sun Yat-sen University.Targeted deep sequencing(NGS 175-Panel)identified gene mutations.Mutation landscape,co-occurrence,mutual exclusivity,and associations with clinical features were analyzed.Kaplan-Meier and Cox proportional-hazards model assessed gene mutation-related prognosis,including overall survival(OS)and event-free survival(EFS).Results:Among 140 AML cases,433 mutations occurred.Top 5 mutated genes were FLT3,CEBPA,NPM1,WT1,and IDH2.WT1,CEBPA,NPM1,and DNMT3A mutation frequencies were significantly higher than those in Western populations.Significant co-occurrence or mutual exclusivity existing between 22 gene pairs,and various gene mutations correlated with clinical features were discovered(all P<0.05).FLT3-ITD(OS:P=0.047,EFS:P=0.097),NRAS(OS:P=0.003,EFS:P=0.300),and WT1(OS:P=0.110,EFS:P=0.004)were associated with poorer OS or EFS.FLT3-ITD positive with WT1 mutations had significantly worse OS and EFS than double-negative or single-positive AML patients(OS:P<0.001,EFS:P=0.005).Meanwhile,FLT3-ITD insertion sites were explored for correlations with clinical characteristics and prognosis,the results showed a significantly poorer OS when FLT3-ITD inserted solely in the juxtamembrane domain(JMDsole),compared to insertions between the juxtamembrane domain and tyrosine kinase domain 1(JMD/TKD1)(P=0.007).Conclusions:AML genetic mutation landscape differ across populations.NRAS,WT1 mutations,and FLT3-ITD and WT1 co-mutations suggest an unfavorable prognosis.