Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications
Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications
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DOI：
10.1182/blood-2013-07-518746
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发表时间：
2014-02-06
期刊：
影响因子：
20.3
通讯作者：
Heuser, Michael
中科院分区：
文献类型：
--
作者：
Thol, Felicitas;Bollin, Robin;Heuser, Michael
内聚蛋白复合物的突变是急性髓性白血病（AML）中一种新的遗传病变，目前还没有很好地表征。在这项研究中，我们通过下一代测序分析了389例统一治疗的AML患者中，所有内聚蛋白复合体成员STAG1、STAG2、SMC1A、SMC3和RAD21突变的频率、临床和预后意义。我们发现共有23例（5.9%）患者在1个凝聚蛋白基因中存在体细胞突变。所有基因突变都是互斥的，其中STAG1（1.8%）、STAG2（1.3%）和SMC3（1.3%）突变最为频繁。任何黏结蛋白复合物突变的患者BAALC表达水平均较低。我们发现影响内聚蛋白复合物和NPM1的突变之间有很强的关联。NPM1和内聚蛋白基因突变的等位基因突变频率相似。总生存率（OS）、无复发生存率（RFS）和完全缓解率（CR）不受内聚蛋白突变的影响（OS：风险比[HR] 0.98； 95%可信区间[CI]， 0.56-1.72 [P = .94]; RFS: HR 0.7; 95% CI, 0.36-1.38 [P = .3]； CR：突变型83% vs野生型76% [P = .45]）。在AML中，内聚蛋白复合物提出了一种受复发性突变影响的新途径。本研究注册号为www.clinicaltrials.gov，编号为#NCT00209833。
Mutations in the cohesin complex are novel, genetic lesions in acute myeloid leukemia (AML) that are not well characterized. In this study, we analyzed the frequency, clinical, and prognostic implications of mutations in STAG1, STAG2, SMC1A, SMC3, and RAD21, all members of the cohesin complex, in a cohort of 389 uniformly treated AML patients by next generation sequencing. We identified a total of 23 patients (5.9%) with somatic mutations in 1 of the cohesin genes. All gene mutations were mutually exclusive, and STAG1 (1.8%), STAG2 (1.3%), and SMC3 (1.3%) were most frequently mutated. Patients with any cohesin complex mutation had lower BAALC expression levels. We found a strong association between mutations affecting the cohesin complex and NPM1. Mutated allele frequencies were similar between NPM1 and cohesin gene mutations. Overall survival (OS), relapse-free survival (RFS), and complete remission rates (CR) were not influenced by the presence of cohesin mutations (OS: hazard ratio [HR] 0.98; 95% confidence interval [CI], 0.56-1.72 [P = .94]; RFS: HR 0.7; 95% CI, 0.36-1.38 [P = .3]; CR: mutated 83% vs wild-type 76% [P = .45]). The cohesin complex presents a novel pathway affected by recurrent mutations in AML. This study is registered at www.clinicaltrials.gov as #NCT00209833.