Mutations affecting mRNAsplicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes
Mutations affecting mRNAsplicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes
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DOI：
10.1182/blood-2011-12-400994
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发表时间：
2012-04-05
期刊：
影响因子：
20.3
通讯作者：
Fontenay, Michaela
中科院分区：
文献类型：
--
作者：
Damm, Frederik;Kosmider, Olivier;Fontenay, Michaela
对一组MDS患者进行了影响4个剪接基因（SF 3B 1、SRSF 2、ZRSR 2和U2 AF 35）的突变检查，并在临床和分子标志物的背景下进行了评价。221名患者中有95名检测到剪接基因突变。这些突变是相互排斥的，不太可能发生在具有复杂细胞遗传学或TP 53突变的患者中。SF 3B 1（mut）患者的血红蛋白水平较低，WBC和血小板计数增加，并且更有可能发生DNMT 3A突变。SRSF 2（mut）患者聚集在RAEB-1和RAEB-2亚型中，并表现出明显的血小板减少。ZRSR 2（mut）患者聚集在国际预后评分系统中的中间-1和中间-2风险组，具有较高的骨髓原始细胞百分比，并且更经常显示孤立的血小板减少症。SRSF 2和ZRSR 2突变在TET 2（mut）患者中更常见。U2 AF 35（mut）患者20号染色体缺失和ASXL 1突变的患病率增加。多变量分析显示，基因型ZRSR 2（mut）/TET 2（wt）的总生存率较低，AML转化率较高（总生存率：风险比= 3.3; 95%CI，1.4-7.7; P = 0.006; AML转化：风险比= 3.6; 95%CI，2-4.2; P = 0.026）。我们的结果表明，剪接基因突变是骨髓增生异常综合征中最常见的分子畸变之一，定义了不同的临床表型，并显示出与靶向转录调节的突变的优先相关性。（血。2012; 119（14）：3211-3218）
A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1(mut) patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2(mut) patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2(mut) patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2(mut) patients. U2AF35(mut) patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2(mut)/TET2(wt) (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation. (Blood. 2012; 119(14): 3211-3218)