不同SF3B1基因型的骨髓增生异常综合征患者实验室及临床特征分析

Laboratory and clinical characteristics of patients with different SF3B1 genotypes in myelodysplastic syndromes

目的探讨不同SF3B1基因型在骨髓增生异常综合征(MDS)患者中的分布情况以及在生存预后中的价值。方法回顾性分析2014年1月至2022年1月南京医科大学第一附属医院诊断的377例初诊 MDS患者临床资料, 根据不同SF3B1基因型将其分为SF3B1野生型(SF3B1WT)317例, 其中男214例, 女103例, 年龄63(49, 71)岁;SF3B1 K700E突变型(SF3B1K700E)39例, 其中男17例, 女22例, 年龄65(52, 73)岁;以及SF3B1非K700E突变型(SF3B1non-K700E)21例, 其中男13例, 女8例, 年龄67(63, 73)岁。采用靶向测序技术检测与MDS相关的20项基因突变情况;Kaplan-Meier法比较3组患者总生存期(OS)和无进展生存期(PFS);Cox回归对MDS进行单因素和多因素分析。结果与SF3B1non-K700E患者相比, SF3B1K700E患者中性粒细胞数更高(P=0.002)。根据IPSS评分, SF3B1K700E患者处于低危和中危-1分组的例数多于SF3B1non-K700E患者数(P=0.023)。利用靶向测序检测20个基因突变情况发现, 与SF3B1WT患者相比, SF3B1K700E患者ASXL1和U2AF1突变率明显降低(P=0.018和P=0.003);与SF3B1non-K700E患者相比, SF3B1K700E患者ASXL1突变率降低(P=0.029)。生存分析显示, 与SF3B1WT和SF3B1non-K700E患者相比, SF3B1K700E患者OS明显延长(P<0.001和P=0.045);在不伴骨髓原始细胞增多(<5%)的MDS患者中, 与SF3B1WT患者相比, SF3B1MUT患者OS和PFS均明显延长(P<0.001和P<0.001);在伴骨髓原始细胞数增多(≥5%)的MDS患者中, SF3B1WT和SF3B1MUT患者OS和PFS差异均无统计学意义(P>0.05);在IPSS评分中危-1的MDS患者中, 与SF3B1WT患者相比, SF3B1K700E患者OS和PFS均明显延长(P=0.010和P=0.013)。多因素回归分析提示SF3B1K700E是影响MDS生存预后的独立保护因素(HR=0.461, 95%CI 0.262~0.811, P=0.007)。结论相比于SF3B1WT患者, SF3B1K700E和SF3B1non-K700E患者预后更好, 其中SF3B1K700EMDS患者的OS明显优于SF3B1non-K700E的患者, 而SF3B1MUT不能克服骨髓原始细胞增多的不良预后, 提示SF3B1突变类型在骨髓原始细胞不增多的MDS患者中具有重要的预后价值。

Objective To analyze the distribution of different SF3B1 genotypes in patients with myelodysplastic syndromes(MDS)and its prognostic value.Methods Totally,377MDS patients who were initially diagnosed in the First Affiliated Hospital of Nanjing Medical University from January 2014 to January 2022 were included in the retrospective analysis.The patients were divided into three different groups according to mutation stcote of SF3B1,including 317 patients with SF3B1 wild type(SF3B1WT)(214 males and 103 females,63(49,71)years old),39 patients with SF3B1 K700E mutation(SF3B1K700E(17 males and 22 females,65(52,73)years old))and 21 patients with SF3B1 non-K700E mutation(SF3B1non-K700E)(13 males and 8 females,67(63,73)years old).MDS-related 20 gene mutations were detected using targeted sequencing technology;Survival curves were constructed by the Kaplan-Meier method;Cox proportional hazards model was established to evaluate different factors at diagnosis on survival by univariate and multivariate analyses..Results Compared with SF3B1non-K700E patients,SF3B1K700E patients had a higher median absolute neutrophil count(P=0.002)and were likely to be in the low/int-1 International Prognostic Scoring System(IPSS)categories(P=0.023).A 20-gene targeted sequencing analysis showed that,compared with SF3B1WT patients,SF3B1K700E patients were associated with lower frequency of ASXL1 and U2AF1 mutations(P=0.018 and P=0.003);while compared with SF3B1non-K700E patients,the frequency of ASXL1 mutation was significantly lower in SF3B1K700E cases(P=0.029).Patients with SF3B1K700E had better overall survival(OS)in comparison with SF3B1WT and SF3B1non-K700E in MDS patients(P<0.001 and P=0.045,respectively).In comparison with SF3B1WT patients,SF3B1MUT patients had more favorable OS and progression-free survival(PFS)in MDS without excess blasts(P<0.001 and P<0.001,respectively),but no significant difference was found in MDS with excess blasts(P>0.05).Compared with SF3B1WT patients,SF3B1K700E patients had superior OS and PFS in the int-1 IPSS category(P=0.010 and P=0.013,respectively).By multivariable analysis,the presence of SF3B1K700Ewas an independent predictor of superior OS(HR=0.461,95%CI 0.262-0.811,P=0.007).Conclusion SF3B1K700E and SF3B1non-K700E patients had significantly improved OS in comparison with SF3B1WT MDS patients.Furthermore,SF3B1K700E patients were associated with a better OS compared with SF3B1non-K700E MDS patients.SF3B1 mutation could not overcome the poor prognostic effect of excess blasts,which highlights the importance of the SF3B1 mutation subtype in risk assessment of MDS without excess blasts.