急性髓系白血病全外显子组测序基因突变特点及其与疗效的关系

Features of gene mutations and its correlation with the therapeutic efficacy by using whole exome sequencing in acute myeloid leukemia

目的探讨急性髓系白血病(AML)患者全外显子组测序(WES)基因突变特点及其与疗效的关系。方法回顾性分析2014年12月至2019年9月安徽医科大学第二附属医院收治的30例AML患者资料,总结WES结果及疾病类型、疾病分型、遗传学预后分层、疗效等情况,比较不同临床特征和遗传学预后分层患者突变类型及突变频率。结果30例AML患者中26例(86.7%)至少发生1个基因突变,其中突变频率>10.0%的基因依次为NRAS、RUNX1、TET2、CEBPA、IDH2、ASXL1,这些突变基因的功能涉及信号通路、转录因子、表观遗传、RNA剪接及其他生物学功能,19例(63.3%)在突变方式上呈现为多种组合的联合突变。在年龄、性别、疾病类型、疾病分型及遗传学预后分层各组中突变率差异均无统计学意义(均P>0.05)。融合基因阳性8例中突变7例,平均突变频率175.0%(14/8);融合基因阴性22例中突变19例,平均突变频率213.6%(47/22);两组间突变频率差异有统计学意义(P=0.001)。持续缓解14例中突变11例,平均突变频率157.1%(22/14);复发10例中突变9例,平均突变频率200.0%(20/10);原发耐药5例均发生突变,平均突变频率300.0%(15/5);3组间突变频率差异有统计学意义(P=0.009)。结论通过WES分析发现,大多数AML患者存在复杂的联合基因突变,且基因突变频率越高提示预后越差。

Objective To investigate the characteristics of gene mutation by using whole exome sequencing(WES)and its relationship with therapeutic efficacy in patients with acute myeloid leukemia(AML).Methods The data of 30 patients with AML from the Second Hospital of Anhui Medical University between December 2014 and September 2019 were retrospectively analyzed;the result of WES,disease type and classification,genetic prognostic stratification and therapeutic efficacy were summarized.The mutation types and mutation frequency of AML patients stratified by the different clinical characteristics and genetic prognosis were compared.Results Among 30 AML patients,26 cases(86.7%)had 1 gene mutation at least.The genes with a mutation frequency more than 10.0%were NRAS,RUNX1,TET2,CEBPA,IDH2 and ASXL1.The function of the mutated genes was involved in signaling pathways,transcription factors,epigenetics,and RNA splicing and other biological functions;in terms of mutation pattern,19 cases(63.3%)of all AML patients mainly presented combined mutations of many combinations.There were no significant differences in mutation rates among age,gender,disease type,disease classification and genetic prognosis stratification groups(all P>0.05).Of the 8 fusion gene positive cases,7 were mutated,the average mutation frequency was 175.0%(14/8).There were 19 mutations in 22 patients with negative fusion gene,the average mutation frequency was 213.6%(47/22),and the difference in mutation frequency between the two groups was statistically significant(P=0.001).Of the 14 cases of continuous remission,11 had mutations,with average mutation frequency of 157.1%(22/14);there were 9 cases of mutations in 10 relapsed patients,and the average mutation frequency was 200.0%(20/10);mutations occurred in 5 patients with primary drug resistance,and the average mutation frequency was 300.0%(15/5);and the difference of mutation frequency among the three groups was statistically significant(P=0.009).Conclusions Through WES analysis,it is found that most AML patients have complex and variable gene mutations;and the higher the gene mutation frequency is,the worse the prognosis of the disease is.