靶向二代测序在骨髓增生异常综合征患者中的诊断及预后意义

The diagnostic and prognostic value of targeted next-generation sequencing in myelodysplastic syndrome

目的探讨靶向二代测序(next-generation sequencing,NGS)在骨髓增生异常综合征(myelodysplastic syndrome,MDS)患者中的诊断及预后意义。方法回顾性分析淮安市第一人民医院血液科2018年1月—2021年9月收治的205例疑诊MDS的血细胞减少患者的靶向NGS数据资料,观察患者的诊断分布、髓系克隆性疾病患者的基因突变特点;采用ROC曲线分析基因突变数目及等位基因变异频率(variant allele fraction,VAF)预测MDS和MDS/MPN的诊断潜能;并采用Kaplan-Meier生存分析法研究突变数目和VAF在初诊MDS患者中的预后意义。结果205例患者包括40例意义未明的特发性血细胞减少症(idiopathic cytopenia of undetermined significance,ICUS)、47例再生障碍性贫血(aplastic anemia,AA)、23例意义未明的克隆性血细胞减少症(clonal cytopenias of undetermined significance,CCUS)、79例MDS、13例骨髓增生异常-骨髓增殖性肿瘤(myelodysplastic/myeloproliferative neoplasms,MDS/MPN)和3例MPN患者。其中,以髓系克隆造血为表现的MDS/MPN、MDS和CCUS 3组患者的VAF的平均值分别为45.12%(7.90%~93.60%)、44.79%(8.70%~99.70%)和34.83%(4.40%~94.60%)(P=0.1778);3组突变数目的平均值分别为2.462(0~7)、1.886(0~7)和1.826(1~4)(P=0.4593)。诊断方面:VAF预测MDS及MDS/MPN的敏感度为78.9%,特异度为80.0%,最佳截断值=6.6%;基因突变数目的敏感度为78.9%,特异度为78.2%,最佳截断值=1;然而2个指标联合并不能提高MDS及MDS/MPN的诊断效能。MDS预后方面:VAF≥57.93%组(n=13)患者较VAF<57.93%组(n=66)的患者预后更差;中位OS显著缩短(9.0个月vs未达到,P=0.0005);中位PFS也显著缩短(11.0个月vs未达到,P=0.0079)。基因突变数目≥2(n=42)的患者较突变数目<2(n=37)的患者预后差;中位OS显著缩短(33.0个月vs未达到,P=0.0265);而中位PFS差异无统计学意义(P=0.6067)。结论本研究的靶向NGS谱简洁实用,基因突变数目和VAF对MDS患者的诊断预测和预后判断具有重要的临床意义。

Objective To explore the diagnostic and prognostic values of targeted next-generation sequencing(NGS)for patients with myelodysplastic syndrome(MDS).Methods A total of 205 cytopenias patients with suspected MDS who were admitted to Department of Hematology,the Affiliated Huai′an No.1 People′s Hospital of Nanjing Medical University from January 2018 to September 2021 were selected and their targeted NGS data were retrospectively analyzed.Their diagnostic distribution and the gene mutation characteristics of patients with myeloid clonal hematopoiesis were observed.A ROC curve was plotted to analyze the diagnostic potential of number of gene mutations and variant allele fraction(VAF)for MDS and MDS/MPN patients.In addition,Kaplan-Meier survival analysis was used to evaluate the prognostic value of VAF and the number of mutations in newly diagnosed MDS patients.Results The 205 patients included 40 patients with idiopathic cytopenia of undetermined significance(ICUS),47 patients with aplastic anemia(AA),23 patients with clonal cytopenias of undetermined significance(CCUS),79 patients with MDS,13 patients with myelodysplastic/myeloproliferative neoplasms(MDS/MPN)and 3 patients with myeloproliferative neoplasms(MPN).For patients in the MDS/MPN,MDS and CCUS groups who were characterized by myeloid clonal hematopoiesis,their mean VAF value was 45.12%(7.90%-93.60%),44.79%(8.70%-99.70%)and 34.83%(4.40%-94.60%),respectively(P=0.1778),while their mean number of mutations was 2.462(0-7),1.886(0-7),and 1.826(1-4),respectively(P=0.4593).Furthermore,VAF had a sensitivity of 78.9%and a specificity of 80.0%,with a cut-off value of 6.60%,when predicting the diagnosis of MDS and MDS/MPN.The number of gene mutations had a sensitivity of 78.9%and a specificity of 78.2%,with a cut-off value of 1,when predicting the diagnosis of MDS and MDS/MPN.However,the combination of the two indicators did not improve the diagnostic efficiency of MDS and MDS/MPN.Moreover,patients with VAF≥57.93%(n=13)showed poorer prognosis than those with VAF<57.93%(n=66),with shorter median overall survival(OS)(9.0 months vs not reached,P=0.0005)and shorter median progression-free survival(PFS)(11.0 months vs not reached,P=0.0079).In contrast,patients with≥2 gene mutations(n=42)presented poorer prognosis than those with<2 gene mutations(n=37),with remarkable shorter median OS(33.0 months vs not reached,P=0.0265),without statistical difference in median PFS(P=0.6067).Conclusions The targeted NGS in this study is simple and practical.The number of gene mutations and VAF can be applied to predict the diagnosis and evalute the prognosis of MDS,with important clinical significance.