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Title: [Gene Profile and Clinical Significance of Concomitant Mutations in CN-AML Patients with CEBPA Mutation].
Author: Zhu J, Kang YF, Gao Y, Wang HW, Hao ZH, Wang HW.
Journal: Zhongguo Shi Yan Xue Ye Xue Za Zhi; 2024 Apr; 32(2):335-341. PubMed ID: 38660833.
Abstract:
OBJECTIVE: To analyze the occurrence of concomitant gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients with CEBPA mutation and its impact on the clinical characteristics and prognosis of the patients. METHODS: 151 newly diagnosed patients with CN-AML in the Second Hospital of Shanxi Medical University from June 2013 to June 2020 were analyzed retrospectively. 34 common genetic mutations associated with hematologic malignancies were detected by next-generation sequencing technology. The occurrence of concomitant gene mutations in patients with CEBPA positive and negative groups was compared, and the correlation between concomitant mutations in different functional groups and the clinical characteristics and prognosis of CN-AML patients with CEBPA mutation was analyzed. RESULTS: In 151 patients with CN-AML, 55 (36.42%) were positive for CEBPA mutation (including 36 cases of CEBPA^dm and 19 cases of CEBPA^sm), of which 41 (74.55%) had co-mutations with other genes. The main mutated genes were GATA2 (25.45%, 14/55), TET2 (21.82%, 12/55), FLT3 (20.00%, 11/55), NRAS (12.73%, 7/55) and WT1 (9.09%, 9/55), etc. Some cases had two or more concomitant gene mutations. Grouping the mutant genes according to their functions showed that CEBPA⁺ group had lower mutation rates of histone methylation (P =0.002) and chromatin modification genes (P =0.002, P =0.033), and higher mutation rates of transcription factors (P =0.037) than CEBPA^- group. In 55 patients with CEBPA⁺ CN-AML, the platelet count at diagnosis in signaling pathway gene mutation-positive group was lower than that in the mutation-negative group (P =0.005), the proportion of bone marrow blasts in transcription factor mutation-positive group was higher than that in the mutation-negative group (P =0.003), and the onset age in DNA methylation gene mutation-positive group and chromatin modifier mutation-positive group was older than that in the mutation-negative group, respectively (P =0.002, P =0.008). DFS of CEBPA⁺ CN-AML patients in signaling pathway gene mutation group was shorter than that in signaling pathway gene mutation-negative group (median DFS: 12 months vs not reached) (P =0.034). Compared with DNA methylation gene mutation-negative group, CEBPA⁺ CN-AML patients with DNA methylation gene mutation had lower CR rate (P =0.025) significantly shorter OS and DFS (median OS: 20 months vs not reached, P =0.006; median DFS: 15 months vs not reached, P =0.049). OS in patients with histone methylation gene mutation was significantly shorter than that in the histone methylation gene mutation-negative group (median OS: 12 months vs 40 months) (P =0.008). Multivariate analysis of prognostic factors showed that the proportion of bone marrow blasts (P =0.046), concomitant DNA methylation gene mutation (P =0.006) and histone methylation gene mutation (P =0.036) were independent risk factors affecting the prognosis. CONCLUSION: CN-AML patients with CEBPA mutation have specific concomitant gene profile, and the concomitant mutations of different functional genes have a certain impact on the clinical characteristics and prognosis of the patients. 题目: CEBPA突变CN-AML伴不同功能基因突变患者的临床特征及预后分析. 目的: 分析CEBPA突变正常核型急性髓系白血病（CN-AML）患者伴随基因突变发生的情况，及其对患者临床特征及预后的影响。. 方法: 回顾性分析2013年6月至2020年6月就诊于山西医科大学第二医院的151例初诊CN-AML患者，通过第二代DNA测序技术检测34种常见血液肿瘤基因突变情况；比较CEBPA⁺与CEBPA^-患者的伴随基因突变发生情况，分析不同功能的基因突变与CEBPA⁺ CN-AML患者临床特征及预后的相关性。. 结果: 在151例CN-AML患者中共检测到55例（36.42%）CEBPA⁺突变（包括36例CEBPA双突变，19例CEBPA单突变），其中41例（74.55%）与其他基因存在共突变，主要突变基因为：GATA2 14 例（25.45%）、 TET2 12 例（21.82%）、FLT3 11例（20.00%）、 NRAS 7例（12.73%）和WT1 5例（9.09%），部分病例同时存在2种及2种以上伴随基因突变。将突变基因按照功能进行分组后发现，CEBPA⁺组较CEBPA^-组具有更低的组蛋白甲基化及染色质修饰基因伴随突变率（P = 0.002，P =0.033）、更高的转录因子基因伴随突变率（P =0.037）。55例CEBPA⁺CN-AML患者中，伴信号通路基因突变阳性组患者初诊时血小板计数低于突变阴性组（P =0.005），伴转录因子基因突变阳性组的骨髓原始细胞比例高于突变阴性组（P =0.003），伴DNA甲基化基因和染色质修饰基因突变阳性组的发病年龄均明显大于相应突变阴性组（P =0.002，P =0.008）。伴随信号通路基因突变阳性组CEBPA⁺ CN-AML患者的DFS短于阴性组（12个月vs 未达到）（P =0.034）。伴DNA甲基化基因突变阳性组较阴性组患者具有更低的CR率（P =0.025），且OS和DFS均显著短于阴性组（中位OS：20个月vs 未达到，P =0.006；中位DFS：15个月vs 未达到，P =0.049）。伴组蛋白甲基化基因突变阳性组患者的OS显著短于阴性组（中位OS：12个月vs 40个月）（P =0.008）。多因素分析显示，骨髓原始细胞比例（HR =4.306）、伴DNA甲基化基因突变（HR =9.917）及组蛋白甲基化基因突变（HR =5.764）是影响CN-AML患者预后的独立危险因素。. 结论: CEBPA⁺CN-AML患者有其特定的伴随基因表达谱，且伴随不同功能基因突变对患者的临床特征及预后有一定影响。.

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