Department of Haematology, UCL Cancer Institute, University College London, 72 Huntley St., London, UK.
J Clin Oncol. 2010 Jun 1;28(16):2739-47. doi: 10.1200/JCO.2009.26.2501. Epub 2010 May 3.
To determine the clinical relevance of mutations in the CCAAT/enhancer binding protein alpha (CEBPA) gene in acute myeloid leukemia (AML) and to examine factors that might modify prognostic impact.
The entire CEBPA coding sequence was screened in 1,427 young adult patients with AML, excluding acute promyelocytic leukemia, using denaturing high-performance liquid chromatography and direct sequencing.
Of 107 patients (7%) with CEBPA mutations, 48 patients (45%) had one mutation (CEBPA-single), and 59 patients (55%) had two mutations (CEBPA-double). The incidence of CEBPA-double patients was similar in intermediate cytogenetic risk patients with and without a normal karyotype (6% and 5%, respectively). CEBPA-double patients had evidence of a lower coincidence with FLT3/ITDs (P = .04) and were highly unlikely to have an NPM1 mutation (P < .0001). CEBPA-double but not CEBPA-single patients had a significantly better overall survival (OS) at 8 years (34%, 31%, and 54% for CEBPA-wild-type [WT], CEBPA-single, and CEBPA-double, respectively, P = .004). This benefit was lost in the presence of a FLT3/ITD (OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-negative patients: 36%, 35%, 59%, respectively, P = .002; OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-positive patients: 26%, 21%, 14%, respectively, P = .05). There was no evidence of any additional favorable benefit for a CEBPA-single mutation in the presence of an NPM1 mutation (OS, 45%, 44%, and 56%, P = .2, for NPM1-positive/CEBPA-WT, NPM1-positive/CEBPA-single, and NPM1-negative/CEBPA-double patients, respectively).
Screening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3/ITD or NPM1 mutation. Only the presence of a CEBPA-double mutation should be used for therapy risk stratification.
确定 CCAAT/增强子结合蛋白α（CEBPA）基因突变在急性髓细胞白血病（AML）中的临床相关性，并研究可能改变预后的因素。
使用变性高效液相色谱法和直接测序法，对 1427 例排除急性早幼粒细胞白血病的年轻成年 AML 患者进行了整个 CEBPA 编码序列的筛选。
在 107 例（7%）CEBPA 突变患者中，48 例（45%）患者存在一个突变（CEBPA-单突变），59 例（55%）患者存在两个突变（CEBPA-双突变）。在伴有或不伴有正常核型的中间细胞遗传学风险患者中，CEBPA-双突变患者的发生率相似（分别为 6%和 5%）。CEBPA-双突变患者与 FLT3/ITD 的一致性较低（P=0.04），且极不可能存在 NPM1 突变（P<0.0001）。CEBPA-双突变患者的总生存（OS）明显优于 CEBPA-野生型（WT）患者（8 年时分别为 34%、31%和 54%，P=0.004）。在存在 FLT3/ITD 的情况下，这种益处丧失（CEBPA-WT、CEBPA-单突变和 CEBPA-双突变 FLT3/ITD 阴性患者的 OS 分别为 36%、35%和 59%，P=0.002；CEBPA-WT、CEBPA-单突变和 CEBPA-双突变 FLT3/ITD 阳性患者的 OS 分别为 26%、21%和 14%，P=0.05）。在存在 NPM1 突变的情况下，CEBPA-单突变不存在任何额外的获益（OS 分别为 45%、44%和 56%，P=0.2，NPM1 阳性/CEBPA-WT、NPM1 阳性/CEBPA-单突变和 NPM1 阴性/CEBPA-双突变患者）。
CEBPA 突变的筛查可以仅限于缺乏 FLT3/ITD 或 NPM1 突变的中间风险细胞遗传学患者。只有 CEBPA-双突变的存在才能用于治疗风险分层。
