伴环状铁粒幼红细胞增多骨髓增生异常综合征基因突变特征及临床意义

Features and clinical significance of gene mutations in patients with myelodysplastic syndromes with ring sideroblasts

目的研究伴环状铁粒幼红细胞增多(RS)的骨髓增生异常综合征(MDS-RS)患者的基因突变特征及其临床意义。方法收集2001年1月至2019年6月于中国医学科学院血液病医院新诊断的255例原发性MDS-RS患者资料。129例采用一代测序、126例采用包含112个血液肿瘤相关基因的二代测序(NGS)进行基因突变分析。结果共193例(75.7%)检出SF3B1突变,其中SF3B1 K700E突变147例(76.2%)。非SF3B1基因突变较常见的有TET2(16.7%)、ASXL1(14.3%)、U2AF1(11.1%)、TP53(7.9%)、SETBP1(6.3%)和RUNX1(6.3%)。RS 5%~<15%患者SETBP1突变率显著高于RS≥15%患者(21.4%对4.5%,P=0.044),其余基因突变率差异无统计学意义(P值均>0.05)。在114例NGS检出SF3B1突变的患者中,RS 5%~<15%患者SF3B1等位基因突变频率(VAF)与骨髓RS比例呈正相关(r=0.486,P=0.078);RS≥15%组SF3B1突变型患者骨髓RS比例显著高于野生型患者[40.0%(15.0%~80.0%)对25.5%(15.0%~82.0%),P<0.001],且SF3B1 VAF与骨髓RS比例呈正相关(P=0.009,rs=0.261)。全部患者SF3B1突变型与野生型年龄、ANC、PLT、平均红细胞体积、RS比例、IPSS-R染色体核型及IPSS-R预后分组等方面差异有统计学意义(P值均<0.05)。多因素分析显示,SF3B1突变是影响总生存(OS)时间的独立良好预后因素(HR=0.265,95%CI 0.077~0.917,P=0.036),TP53突变是独立不良预后因素(HR=6.272,95%CI 1.725~22.809,P=0.005)。根据SF3B1和TP53突变状态将MDS-RS患者分为四组:SF3B1和TP53均突变组、SF3B1和TP53均野生组、SF3B1野生伴TP53突变组及SF3B1突变伴TP53野生组,四组患者OS时间差异显著(P<0.001)。组间两两比较显示SF3B1突变伴TP53野生组OS时间显著长于SF3B1野生伴TP53突变组、SF3B1和TP53野生组,而与SF3B1和TP53均突变组比较差异无统计学意义。结论SF3B1突变在MDS-RS中的发生率较高,几乎均是错义突变,以K700E突变最为常见。SF3B1突变是MDS-RS患者生存的独立良好预后因素,TP53突变是独立不良预后因素,二者联合可更精细地指导MDS-RS患者预后分层。

Objective To explore the features and clinical significance of gene mutations in patients with myelodysplastic syndromes with ring sideroblasts(MDS-RS).Methods A total of 255 newly diagnosed primary MDS-RS patients were retrospectively reviewed from our center from January2001 to June 2019.SF3B1 gene mutations were detected by Sanger sequencing in 129 patients,and next generation sequencing(NGS)was performed in the other 126 patients using a set of selected 112-genes.Results A total of 193(75.7%)patients presented with SF3B1 mutation,predominantly mutant at amino acid position 700(K700E)(n=147,76.2%).Non-SF3B1 gene mutations were TET2(16.7%),ASXL1(14.3%),U2AF1(11.1%),TP53(7.9%),SETBP1(6.3%),and RUNX1(6.3%).RS 5%-<15%patients had a higher SETBP1 mutation frequency than RS≥15%patients(21.4%vs 4.5%,P=0.044).Mutation frequencies of other genes were similar in both groups(all P>0.05).SF3B1 variant allele frequencies(VAF)had positive correlation with marrow RS percentage but without statistical significance in RS 5%-<15%group(P=0.078,r=0.486).SF3B1 mutant patients presented with higher marrow RS percentage compared with wild-type patients[40.0%(15.0%-80.0%)vs 25.5%(15.0%-82.0%),P<0.001],and SF3B1 VAF positively correlated with RS percentage(P=0.009,rs=0.261)in RS≥15%group.Age,ANC,PLT,mean RBC corpuscular volume,RS percentage,IPSS-R cytogenetics,and IPSS-R risk score were significantly different between patients with SF3B1 mutations and wild-type SF3B1(all P<0.05).Multivariable survival analyses adjusted by age and IPSS-R cytogenetics revealed that SF3B1 mutation was an independent favorable prognostic factor(HR=0.265,95%CI 0.077-0.917,P=0.036),and TP53 mutation was an adverse variable independent of SF3B1 mutation(HR=6.272,95%CI 1.725-22.809,P=0.005).According to the mutant status of SF3B1 and TP53,MDS-RS patients were categorized into 4 groups,namely,with SF3B1 and TP53 mutation,with wild-type SF3B1 and TP53,with wild-type SF3B1 but TP53 mutation,and with SF3B1 mutation but wild-type TP53.There was a significant difference for OS among these 4 groups(P<0.001).The former 3 groups showed no significant difference in OS in multiple comparisons.However,the SF3B1 mutation but wild-type TP53 group had a better OS than wild-type SF3B1 but TP53 mutation group and wild-type SF3B1 and TP53 group,whereas a similar OS compared with SF3B1 and TP53 mutation group.Conclusion SF3B1 mutations were prevalent in MDS-RS patients with the most common mutation at amino acid position 700(K700E).SF3B1 mutation was an independent favorable prognostic variable,whereas TP53 mutation was an independent adverse variable.SF3B1 mutation could coordinate with TP53 mutation for more sophisticated prognosis stratification in MDS-RS patients.