基于多基因测序研究伴CEBPA-bZIP突变的成人正常核型急性髓系白血病的基因突变谱及危险分层  

Genetic Mutation Profile and Risk Stratification of Cytogenetically Normal Acute Myeloid Leukemia with CEBPA-bZIP Mutations Based on Multi-Gene Sequencing

作　　者：曹雷茗 廖明玥 周亚兰 江浩[1] 江倩[1] 常英军[1] 许兰平[1] 张晓辉[1] 黄晓军[1,2] 阮国瑞 CAO Lei-Ming;LIAO Ming-Yue;ZHOU Ya-Lan;JIANG Hao;JIANG Qian;CHANG Ying-Jun;XU Lan-Ping;ZHANG Xiao-Hui;HUANG Xiao-Jun;RUAN Guo-Rui(Peking University People′sHospital,Peking University Institute of Hematology,National Clinical Research Center for Hematologic Disease,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation,Peking University;Peking-Tsinghua Center for Life Sciences,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing 100044,China)

机构地区：[1]北京大学人民医院,北京大学血液病研究所,国家血液系统疾病临床医学研究中心,造血干细胞移植治疗血液病北京市重点实验室 [2]北大-清华生命科学联合中心,前沿交叉学科研究院,北京100044

出　　处：《中国实验血液学杂志》2024年第6期1631-1637,共7页Journal of Experimental Hematology

基　　金：国家自然科学基金(82100169,81770156);国家自然科学基金创新研究群体(81621001)。

摘　　要：目的:探讨伴CEBPA-bZIP突变的成人正常核型急性髓系白血病(CN-AML)患者的基因突变谱及预后意义。方法:对141例伴CEBPA-bZIP突变的成人CN-AML初诊骨髓DNA样本进行靶区测序,结合突变信息及临床数据构建基于无白血病生存率的Nomogram模型。根据预后因素进行危险分层,采用Kaplan-Meier法探讨风险调整的缓解后治疗的获益程度。结果:经多因素Cox分析后4个因素被纳入本研究的Nomogram模型,由此得到一个风险评分计算的方程:危险分数=1.3002×WBC(≥18.77×10^(9)/L)+1.4065×CSF3R突变阳性+2.6489×KMT2A突变阳性+1.0128×DNA甲基化相关基因突变阳性。根据该模型进一步将患者分为低风险组46例(分数=0)和高风险组95例(分数>0),预后分析结果表明,高风险组中接受异基因造血干细胞移植的患者5年无白血病生存率、5年总体生存率和5年累积复发率分别93.5%、97.1%和3.5%,接受维持化疗的患者分别为32.9%、70.5%和63.4%,其差异均有统计学意义(均P<0.05),异基因造血干细胞移植可显著改善患者的预后,而在低风险组中并未观察到类似的获益。结论:伴CEBPA-bZIP突变的成人CN-AML具有复杂的共突变模式,基于CFS3R、KMT2A和DNA甲基化相关基因的突变情况联合白细胞水平构建的Nomogram模型可将该组患者进一步细分为相对低风险组和相对高风险组;对于高风险组患者,推荐异基因造血干细胞移植作为其缓解后的治疗方案。以上数据将有助于伴CEBPA-bZIP突变的成人CN-AML的预后评估及治疗决策。Objective:To evaluate the gene mutation profile and prognostic significance of adult cytogenetically normal acute myeloid leukemia(CN-AML)with CEBPA-bZIP mutation.Methods:Targeted sequencing was implemented on the diagnostic bone marrow DNA samples of 141 adult CN-AML subjects with CEBPA-bZIP mutation.The nomogram model for leukemia-free survival(LFS)rate was generated by combining genetic abnormalities and clinical data.Risk stratification was conducted based on prognostic variables and the effect of risk-adjusted consolidation therapy was investigated by Kaplan-Meier method.Results:Four variables were finally included in our nomogram model after multivariate Cox analysis,and an equation for risk score calculation was obtained,risk score=1.3002×white blood cell(WBC)(≥18.77×10^(9)/L)+1.4065×CSF3R mutation positive+2.6489×KMT2A mutation positive+1.0128×DNAmethylation-related genes mutation positive.According to the nomogram model,patients were further divided into low-risk group(score=0,n=46)and high-risk group(score>0,n=95).Prognostic analysis showed that the 5-year LFS rate,5-year overall survival(OS)rate,and 5-year cumulative incidence of relapse(CIR)of patients who received allogeneic hematopoietic stem cell transplantation(allo-HSCT)in the high-risk group were 93.5%,97.1%,and 3.5%,while those in patients who received maintenance chemotherapy were 32.9%,70.5%,and 63.4%,respectively.The differences were statistically significant(all P<0.05).Allo-HSCT could significantly improve the prognosis of patients in high-risk group.However,no corresponding benefit was observed in the low-risk group.Conclusion:Adult CN-AML with CEBPA-bZIP mutation has a complex co-mutation pattern.The nomogram model based on mutations of CFS3R,KMT2A and DNA methylation-related genes together with WBC count can further divide this subset of patients into a relatively low-risk group and a relatively high-risk group.For individuals in the high-risk group,allo-HSCT is proposed as post-remission therapy.The above data will benefit the p

关 键 词：二代测序 急性髓系白血病 正常核型 CEBPA-bZIP突变 Nomogram模型 

分 类 号：R733.71[医药卫生—肿瘤]