Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity
Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity
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DOI：
10.1182/blood-2010-09-307280
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发表时间：
2011-02-24
期刊：
影响因子：
20.3
通讯作者：
Doehner, Konstanze
中科院分区：
文献类型：
--
作者：
Taskesen, Erdogan;Bullinger, Lars;Doehner, Konstanze
我们在1182例细胞遗传学正常的急性髓性白血病（AML）患者（16-60岁）中评估了CCAAT/增强子结合蛋白α (CEBPA)双突变（CEBPA(dm)）与单突变（CEBPA(sm)）的并发基因突变、临床结果和基因表达特征。我们确定了151例（12.8%）CEBPA突变患者（91例CEBPA（dm）和60例CEBPA(sm)）。种系突变发生率为7%(5 / 71)，包括3个c端突变。CEBPA（dm）患者的并发突变频率低于CEBPA（sm）患者（P < 0.0001）。与CEBPA相比，这两个组的预后都较好（wt）（5年总生存率[OS]分别为63%和56% vs 39%； P分别< 0.0001和P = 0.05）。然而，在多变量分析中，只有CEBPA（dm）是有利OS结果的预后因素（风险比[HR] 0.36, P < 0.0001；无事件生存期，HR 0.41, P < 0.0001；无复发生存期，HR 0.55, P = .001）。CEBPA（sm）的结果主要由并发的NPM1和/或FLT3内部串联重复突变决定。无监督和有监督的GEP分析显示，CEBPA(dm) AML （n = 42）而非CEBPA(sm) AML （n = 18）表达了一个独特的基因特征。CEBPA(dm) AML的25个探针组预测标记显示100%的敏感性和特异性。基于这些发现，我们建议将CEBPA（dm）与CEBPA(sm) AML区分开来，并将其视为AML分类中的一个独立实体。(血。2011;117 (8):2469 - 2475)
We evaluated concurrent gene mutations, clinical outcome, and gene expression signatures of CCAAT/enhancer binding protein alpha (CEBPA) double mutations (CEBPA(dm)) versus single mutations (CEBPA(sm)) in 1182 cytogenetically normal acute myeloid leukemia (AML) patients (16-60 years of age). We identified 151 (12.8%) patients with CEBPA mutations (91 CEBPA(dm) and 60 CEBPA(sm)). The incidence of germline mutations was 7% (5 of 71), including 3 C-terminal mutations. CEBPA(dm) patients had a lower frequency of concur-rent mutations than CEBPA(sm) patients (P < .0001). Both, groups were associated with a favorable outcome compared with CEBPA(wt) (5-year overall survival [OS] 63% and 56% vs 39%; P < .0001 and P = .05, respectively). However, in multivariable analysis only CEBPA(dm) was a prognostic factor for favorable OS outcome (hazard ratio [HR] 0.36, P < .0001; event-free survival, HR 0.41, P < .0001; relapse-free survival, HR 0.55, P = .001). Outcome in CEBPA(sm) is dominated by concurrent NPM1 and/or FLT3 internal tandem duplication mutations. Unsupervised and supervised GEP analyses showed that CEBPA(dm) AML (n = 42), but not CEBPA(sm) AML (n = 18), expressed a unique gene signature. A 25-probe set prediction signature for CEBPA(dm) AML showed 100% sensitivity and specificity. Based on these findings, we propose that CEBPA(dm) should be clearly defined from CEBPA(sm) AML and considered as a separate entity in the classification of AML. (Blood. 2011;117(8):2469-2475)