Pabst Thomas, Eyholzer Marianne, Haefliger Simon, Schardt Julian, Mueller Beatrice U
Department of Medical Oncology, University Hospital, Bern, Switzerland.
J Clin Oncol. 2008 Nov 1;26(31):5088-93. doi: 10.1200/JCO.2008.16.5563. Epub 2008 Sep 2.
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.
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.
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.
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.
转录因子CCAAT/增强子结合蛋白α（CEBPA）对正常髓系分化至关重要。在急性髓系白血病（AML）患者亚组中发现了CEBPA基因的突变。最近，有三个家族被报道，其中几名家族成员存在CEBPA种系突变，随后发展为AML。虽然家族性AML被认为是罕见事件，但AML中CEBPA种系突变的频率尚不清楚。
在本研究中，我们在诊断时对187例连续的AML患者进行了CEBPA突变筛查。我们检测到18例（9.6%）有CEBPA突变的患者。然后我们分析了这些患者的缓解期样本和组成性DNA。
我们发现18例有CEBPA突变的AML患者中有2例（11.1%）携带种系N端移码CEBPA突变。有趣的是，这两名患者家族中的其他成员也受到了AML的影响，并且在这些患者中也观察到了种系CEBPA突变。两个家族中有种系CEBPA突变的AML患者的其他体细胞突变包括两名患者的框内C端CEBPA突变、一名患者的两个非沉默CEBPA点突变和一名患者的7号染色体单体。
据我们所知，本研究首次表明，在有CEBPA突变的AML患者中经常观察到种系CEBPA突变。包括先前报道的有种系CEBPA突变的家族，额外的体细胞CEBPA突变是有种系CEBPA突变的AML中常见的第二个事件。我们的数据强烈表明，种系CEBPA突变易患AML，而额外的体细胞CEBPA突变有助于疾病的发展。
