Mutaome profile of 10 common mutated genes in refractory and relapsed acute myeloid leukemia

目的 探讨难治复发急性髓系白血病(AML)患者中常见的10种突变基因发生的规律.方法 选取难治复发AML患者148例.基因测序检测并分析患者骨髓样本中10种常见突变基因,包括激酶类基因FLT3和KIT,转录因子基因CEBPA、NPM1和PHF6,以及表观遗传类基因ASXL1、DNMT3A、IDH1、IDH2和TET2.结果 在62.16％(92/148)的患者中检测到上述基因突变阳性,其中10.14％(15/148)的患者同时携带多个基因的突变.FLT3-ITD突变率最高(19.59％,29/148),其次为KIT(12.84％,19/148)和CEBPA(11.49％,17/148)突变.KIT突变常单独出现,而IDH1/2突变常伴随其他基因突变.激酶类基因FLT3和KIT突变互斥,转录因子基因和表观遗传基因也存在同类互斥现象.以35岁为界限分组,≤35岁的患者多携带单个基因的突变[61.77％(63/102)比31.11％(14/45),P＜ 0.05],而＞35岁的患者多个基因突变(≥2个)的携带率高[20.00％(9/45)比4.90％(5/102),P＜ 0.05].＞35岁患者组中NPM1突变率高于≤35岁组[20.00％(9/45)比2.94％(3/102),P＜ 0.05].结论 研究发现难治复发AML患者中常见基因突变的组合具有一定的规律,与基因的功能分类和患者的年龄有关.Objective To investigate the mutaome profiling of the 10 common mutated genes in refractory and relapsed acute myeloid leukemia (AML) patients.Methods 148 patients who were diagnosed as refractory and relapsed AML were enrolled.Mutations of 10 common mutated genes were analyzed in bone marrow samples by Sanger sequencing,including kinase genes FLT3 and KIT,transcription factor genes CEBPA,NPM1 and PHF6,as well as epigenetic regulation genes ASXL1,DNMT3A,IDH1,IDH2 and TET2.Results Mutations of the 10 genes were detected in 62.16 ％ (92/148) of the patients,and 10.14 ％ (15/148) of patients carried mutations of more than one gene.FLT3-ITD was the most frequently mutated gene,which was detected in 19.59 ％ (29/148) cases,followed by KIT (12.84 ％,19/148) and CEBPA (11.49 ％,17/148) mutations.KIT mutations usually occurred alone,while IDH1 and IDH2 often mutated accompanied with other genes.Mutations of kinase genes,including FLT3 and KIT,were mutually exclusive.Transcription factor genes and epigenetic regulation genes seldom mutated with genes of the same functional classification group.When patients were divided into two groups according to age,patients in the group of ≤ 35 years were more likely to harbor mutations of the single gene [61.77 ％ (63/102) vs 31.11％ (14/45),P ＜ 0.05],while individuals in the group of ＞ 35 years often carried mutations of more genes than one gene [20.00 ％ (9/45) vs 4.90 ％ (5/102),P ＜ 0.05].The mutation frequency of NPM1 in ＞ 35 years group was higher than that in ≤ 35 years group [20.00 ％ (9/45) vs 2.94 ％ (3/102),P ＜ 0.05].Conclusions There were certain rules in the mutaome profiling of refractory and relapsed AML patients,which was related to the function classification of genes and age of patients.国家自然科学基金青年科学基金5261-2642