The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML
The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML
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DOI：
10.1002/ajh.25517
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发表时间：
2019-08-01
影响因子：
12.8
通讯作者：
Traer, Elie
中科院分区：
文献类型：
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作者：
Dunlap, Jennifer B.;Leonard, Jessica;Traer, Elie
急性髓系白血病(AML)是一种遗传异质性疾病，其临床病程可通过反复出现的细胞遗传学异常和/或基因突变来预测。NPM1插入突变定义了最大的独特遗传亚集，类似于30%的AML，如果没有(或低等位基因比率)Flt3内部串联重复(Flt3ITD)突变，NPM1插入突变被认为是一个有利的危险标记。然而，与40%没有Flt3ITD的NPM1突变患者一样，ITD仍然复发，驱动复发的因素仍然不完全清楚。我们使用下一代测序小组来检查诊断时的突变；治疗后突变的清除，以及复发时突变的获得/丢失，以确定导致复发的突变的优先顺序。在我们发现的数据集中，NPM1、DNMT3A和IDH1/2的三个突变显示出总体存活率较低的趋势，并且在大型独立验证队列中与OS减少显著相关。对相对变异等位基因频率的分析表明，在获得NPM1突变之前，DNMT3A和IDH1/2的早期突变和扩张会增加复发的风险。这部分患者可能受益于异基因干细胞移植或IDH抑制剂的临床试验。
Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a clinical course predicted by recurrent cytogenetic abnormalities and/or gene mutations. The NPM1 insertion mutations define the largest distinct genetic subset, similar to 30% of AML, and is considered a favorable risk marker if there is no (or low allelic ratio) FLT3 internal tandem duplication (FLT3 ITD) mutation. However, similar to 40% of patients with mutated NPM1 without FLT3 ITD still relapse, and the factors that drive relapse are still not fully understood. We used a next-generation sequencing panel to examine mutations at diagnosis; clearance of mutations after therapy, and gain/loss of mutations at relapse to prioritize mutations that contribute to relapse. Triple mutation of NPM1, DNMT3A and IDH1/2 showed a trend towards inferior overall survival in our discovery dataset, and was significantly associated with reduced OS in a large independent validation cohort. Analysis of relative variant allele frequencies suggests that early mutation and expansion of DNMT3A and IDH1/2 prior to acquisition of NPM1 mutation leads to increased risk of relapse. This subset of patients may benefit from allogeneic stem cell transplant or clinical trials with IDH inhibitors.