骨髓增生异常综合征基因突变特征及突变负荷相关临床分析

Clinical analysis of gene mutation characteristics and mutation burden in myelodysplastic syndrome

目的探讨骨髓增生异常综合征(MDS)基因突变特征及突变负荷与患者一般情况、疾病亚型、染色体核型间的关系和临床价值。方法采用高通量测序靶向检测以2016年1月至2019年4月于河南省肿瘤医院就诊的191例MDS患者和9例MDS继发急性髓细胞白血病(SAML)患者的65种血液肿瘤相关基因,分析异常基因特点、突变负荷,及与疾病亚型、染色体核型和患者年龄等的关系。结果共有148例(77.5%)MDS患者发现突变,其中包含47种异常基因和186个突变位点。9例SAML患者均发现基因突变,突变个数显著高于MDS患者(χ2=11.911,P=0.018)。MDS患者检出异常基因中,U2AF1(37.3%)和ASXL1(41.6%)等突变频率较高,且不同异常基因间突变负荷间差异有统计学意义(F=91.946,P<0.001)。不同亚型MDS患者,基因突变个数存在差异,EB-2型基因突变个数最多[(2.2±1.5)个]。在SLD、MLD、EB-1和EB-2中,携带≥3个突变的比例逐渐增高(χ2=52.471,P=0.037)。TP53突变与异常核型相关(rφ=0.177,P=0.019),特别与复杂核型相关(rφ=0.440,P<0.001),而NPM1突变与正常染色体核型相关(rφ=0.173,P=0.024)。30岁以下患者携带突变个数最少,突变个数随着年龄增大而增加,其中60~79岁患者的突变个数最多(P=0.017),表观遗传学相关基因随年龄增长而突变频率增加(P=0.041)。结论MDS相关基因突变特征及其突变负荷与疾病的亚型、染色体核型及患者年龄等临床因素密切相关。

Objective To investigate the relationship between gene mutation characteristics,mutation burden and general condition,disease subtype and karyotype of patients with myelodysplastic syndrome(MDS),and its clinical value.Methods High-throughput sequencing was used to detect 65 blood tumor-related genes in 191 MDS patients and 9 secondary acute myelocytic leukemia patitents(SAML),and to analyze the characteristics of abnormal genes,mutation burden,as well as the relationship with disease subtypes,chromosome karyotypes and age.Results Mutations were found in 148 patients(77.5%),including 47 abnormal genes and 186 mutation sites.And gene mutations were found in 9 SAML patients,the number of mutations was significantly higher than that in MDS patients(χ2=11.911,P=0.018).Among the abnormal genes,the mutation frequency of U2AF1(37.3%)and ASXL1(41.6%)were higher,and there were significant differences in mutation burden among different abnormal genes(F=91.946,P<0.001).There were differences in the number of gene mutations among different subtypes of MDS,and the number of EB-2 gene mutations was the highest(2.2±1.5).In SLD,MLD,EB-1 and EB-2,the proportion of carrying≥3 mutations increased gradually(χ2=52.471,P=0.037).TP53 mutation was associated with abnormal karyotype(rφ=0.177,P=0.019),especially with complex karyotype(rφ=0.440,P<0.001),while NPM1 mutation is associated with normal karyotype(rφ=0.173,P=0.024).The number of mutations carried by patients under 30 years old was the least,and the number of mutations increased with the increase of age.The number of mutations was the most in patients aged 60 to 79 years old(P=0.017),and the mutation frequency of epigenetic related genes increased with the increase of age(P=0.041).Conclusions The mutation characteristics and mutation load of MDS-related genes are closely related to clinical factors such as disease subtype,chromosome karyotype and patient age.