【背景】:骨髓增生异常综合征(myelodysplastic syndromes，MDS)常有多个基 因突变，且基因突变影响患者生存预后。SF381突变的MDS患者骨髓环状铁粒幼红细胞(ring sideroblasts，RS)比例增高，总体生存预后较好。WHO (2016)诊断标准建议甜弓BJ『突变但不伴有原始细胞增多(<5％)的MDS患者仅需骨髓RS三5％即可诊断为伴环状铁粒幼红细胞增多的骨髓增生异常综合征(MDS with ring sideroblasts，MDS-RS)。
【目的】:研究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201 9年6月于我中心新诊断的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114个血液肿瘤相关 基因的靶向二代测序(nextgenerationsequence，NGS)进行基因突变分析。
【结果】:共193例(75．7％)检出SF381突变，其中SF381 K700E突变147例(76．2％)，5％I5％患者各类型SF381突变检出率无显著 差异(尸值均>0．05)。非SF381基因突变较常见的有TET2(16．7％)、ASXLl(14．3％)、U弘F／(11．1％)、即53(7．9％)、SETBPJ(6．3％)和R(WXf(6．3％)。 5％sRS<15％患者SETBPl突变率显著高于RS≥15％患者(21．4％对4．5％，P=0．044)，其余基因突变率无显著差异(尸值均>0．05)。5％虫S<15％患者SF381突变负荷与骨髓RS比例呈正相关但无统计学意义(仁0．078，r=0．486)，而RS_>15％组中SF381突变患者骨髓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SF381突变负荷与骨髓RS比例呈正相关(尸=0．009，r=0．261)。全部患者及RS≥15％ 患者中SF381突变型与野生型患者年龄、中性粒细胞计数(absolute neutrophil count，ANC)、血小板(platelet，PLT)、平均红细胞体积(mean corpuscular volume，MCV)、RS比例、IPSS．R染色体核型及IPSS．R预后 分组等方面差异显著(P值均<0．05)，而5％5RS<15％和RS≥15％患者主要临床和实验室特征无显著差异。5％15％患者总体生存(overall survival，OS)时间无显著差异(卢0．314)。单因素及纳入年龄、IPSS．R染色体核型等临床参数的多因素分析表明，SF381突变是影响OS时间的独立良好预后因素(HR=0．265，95％C10．077～0．917，P=-0．036)，TP53突变是独立不良预后因素(HR=6．272，95％C11．725～22．809，P=-0．005)。根据SF381和TP53突变状态，MDS．RS患者分为四组：SF3BI和TP53均突变组、甜召BJ和TP53均野生组、SF381野生伴TP53突变组及SF381突变伴TP53野生组，四组患者OS时间差异显著(尸<0．001)。组间两两比较显示前三组患者间OS时间无显著差异，但SF381突变伴即”野生组OS时间显著长于SF3B．，野生伴TP53突变组、SF381和TP53野生组，而与SF381和TP53均突变组比较无显著差异。
【结论】:SF381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。5％15％MDS．RS患者基因突变谱系、临床特征、生存预后大体相似。SF381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。

Background: Genetic mutations were prevalent in myelodysplastic syndromes(MDS)，and might influence the prognosis of MDS subjects．MDS subjects harboring SF3B 1 mutation presented with higher marrow ring sideroblasts(RS)percentage and a better overall survival．According to WHO(20 1 6)classification，a diagnosis of MDS with ring sideroblasts(MDS-RS)might be made if RS comprise as few as 5％of nucleated erythroid cells in MDS subjects with SF3B 1 mutation and
without excess blasts(<5％)．
Objective: To explore the features and clinical significance of gene mutations in patients with myeIodyspIastic syndromes with MDS-RS．
Methods: A total of 255 newlydiagnosed primaryMDS-RS patients were retrospectively reviewed from our center from January 2001 to June 2019．SF381 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: 193(75.7％)patients presented with SF381 mutation，predominantly mutant at amino acid position 700(K700E)(n=147，76.2％)．The frequencies ofvarious type of SF381 mutation had no significant difference between 5％ RS>15％groups(all P value>0.05)．Non-SF381 gene mutations were TET2 (16.7％)，ASXLl(14.3％)，U2AFl(11.1％)，TP53(7.9％)，SETBPl(6.3％)and RUNXl(6.3％)．5％15％patients(21.4％VS 4.5％，P=0.044)，mutation frequencies of other genes were similar in both groups(all P vale>0.05)．SF381 variant allele frequencies(VAF)had positive correlation with marrow RS percentage but without statistical significance in 5％SRS<15 group(P=0.078， r=0.486)．SF381 mutant patients presented with higher marrow RS percentage compared to wild-type patients[40.O％(15.0～80.0％)VS 25.5％(15.O～82.O％)，P<0.00 1]，and SF381 VAF positively correlated with RS percentage(P=0.009，r=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 SF381 mutations and wild-type SF381 in all patients or RS>15％patients ( all P value15％．There was no significant difference for overall survival(os)between patients with 5％SRS<15％and RS>l5％(P=0.314)．Univariable and multivariable survival analyses adjusted by age and 1PSS-R cytogenetics displayed that SF381 mutation was an independent favorable prognostic factor (HR=0．265，95％C10.077-0.917，P=-0.036)，and TP53 mutation was an adverse variable independent of SF381 mutation(HR=6.272，95％C／1.725-22.809，P=0.005)．According to the mutant status of SF381 and TP53、MDS—RS patients were categorized into four groups，namely group with SF381 and TP53 mutation， with wild type SF381 and TP53，with wild type SF381 but TP53 mutation and with SF381 mutation but wild type TP53．There was significant difference for OS among these four groups (p<0.001)．The former three groups showed no significant difference in OS in multiple comparison．However,the SF381 mutation but wild type TP53 group had a better OS than wild type SF3BI but TP53 mutation group and wild type SF381 and TP53 group，whereas a similar OS compared to SF381 and TP5 3 mutation group． 
Conelusion SF381 mutations were prevalent in MDS-RS patients with the most common mutation at amino acid position 700(K700E)．5％l5％ patients had similar mutation spectrum，clinical features and prognosis．SF381 mutation was an independent favorable prognostic variable，whereas TP53 mutation was an independent adverse variable．SF381 mutation could coordinate with TP53 mutation for more sophisticated prognosis stratification in MDS—RS patients．