Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;
Blood. 2014 Feb 6;123(6):914-20. doi: 10.1182/blood-2013-07-518746. Epub 2013 Dec 13.
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.
在急性髓系白血病 (AML) 中，黏合蛋白复合物的突变是一种新的遗传病变，尚未得到很好的描述。在这项研究中，我们通过下一代测序分析了 389 名经统一治疗的 AML 患者队列中黏合蛋白复合物的成员 STAG1、STAG2、SMC1A、SMC3 和 RAD21 中突变的频率、临床和预后意义。我们总共鉴定出 23 名患者（5.9%）存在 1 个黏合蛋白基因的体细胞突变。所有基因突变均相互排斥，STAG1（1.8%）、STAG2（1.3%）和 SMC3（1.3%）突变最为常见。存在黏合蛋白复合物突变的患者 BAALC 表达水平较低。我们发现黏合蛋白复合物突变与 NPM1 之间存在很强的关联。NPM1 和黏合蛋白基因突变的突变等位基因频率相似。黏合蛋白突变的存在并不影响总生存（OS）、无复发生存（RFS）和完全缓解率（CR）（OS：风险比 [HR] 0.98；95%置信区间 [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]）。黏合蛋白复合物代表了 AML 中受反复突变影响的新途径。本研究在 www.clinicaltrials.gov 注册，编号为 #NCT00209833。
