Somatic CEBPA Mutations Are a Frequent Second Event in Families With Germline CEBPA Mutations and Familial Acute Myeloid Leukemia
Somatic CEBPA Mutations Are a Frequent Second Event in Families With Germline CEBPA Mutations and Familial Acute Myeloid Leukemia
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DOI：
10.1200/jco.2008.16.5563
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发表时间：
2008-11-01
影响因子：
45.3
通讯作者：
Mueller, Beatrice U.
中科院分区：
文献类型：
--
作者：
Pabst, Thomas;Eyholzer, Marianne;Mueller, Beatrice U.
目的转录因子CCAAT/增强子结合蛋白-α（CEBPA）对正常骨髓分化至关重要。CEBPA基因突变在急性髓细胞白血病（AML）患者的亚群中发现。最近，有报道称，三个家庭的多名家庭成员出现种系CEBPA突变，随后患上了AML。而家族性AML被认为是一种罕见的事件，CEBPA种系突变的频率在AML.Patients和方法在这项研究中，我们筛选了187个连续的AML患者CEBPA突变诊断。我们检测到18例（9.6%）CEBPA突变。然后，我们分析缓解样品和组成性DNA从这些patients.Results我们发现，两个（11.1%）的18例AML患者与CEBPA突变进行生殖系N端移码CEBPA突变。有趣的是，这两名患者家族中的其他成员都受到AML的影响，并且在这些患者中也观察到生殖系CEBPA突变。额外的体细胞突变的AML患者与生殖细胞CEBPA突变的两个家庭包括在框内的C-末端CEBPA突变的2例患者，两个非沉默CEBPA点突变的1例患者，和单体7在1 patient.Conclusion这项研究表明，为我们所知的第一次，生殖细胞CEBPA突变是经常观察到的AML患者与CEBPA突变。包括先前报道的具有生殖系CEBPA突变的家族，额外的体细胞CEBPA突变代表了具有生殖系CEBPA突变的AML中的频繁的第二事件。我们的数据有力地表明，胚系CEBPA突变易患AML，额外的体细胞CEBPA突变有助于疾病的发展。J Clin Oncol 26：5088-5093. (C)2008年美国临床肿瘤学会
Purpose The transcription factor CCAAT/enhancer binding protein-alpha (CEBPA) is crucial for normal myeloid differentiation. Mutations in the CEBPA gene are found in subsets of patients with acute myeloid leukemia (AML). Recently, three families were reported in whom several family members had germline CEBPA mutations and subsequently developed AML. Whereas familial AML is considered a rare event, the frequency of CEBPA germline mutations in AML is not known.Patients and Methods In this study, we screened 187 consecutive AML patients for CEBPA mutations at diagnosis. We detected 18 patients (9.6%) with CEBPA mutations. We then analyzed remission samples and constitutive DNA from these patients.Results We found that two (11.1%) of 18 AML patients with CEBPA mutations carried a germline N-terminal frameshift CEBPA mutation. Interestingly, additional members in the families of both of these patients have been affected by AML, and the germline CEBPA mutations were also observed in these patients. Additional somatic mutations in AML patients with germline CEBPA mutations in the two families comprised in-frame C-terminal CEBPA mutations in two patients, two nonsilent CEBPA point mutations in one patient, and monosomy 7 in one patient.Conclusion This study shows, for the first time to our knowledge, that germline CEBPA mutations are frequently observed among AML patients with CEBPA mutations. Including the families with germline CEBPA mutations reported previously, additional somatic CEBPA mutations represent a frequent second event in AML with germline CEBPA mutations. Our data strongly indicate that germline CEBPA mutations predispose to AML and that additional somatic CEBPA mutations contribute to the development of the disease. J Clin Oncol 26: 5088-5093. (C) 2008 by American Society of Clinical Oncology