Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia
Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia
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DOI：
10.1182/blood-2016-01-693879
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发表时间：
2016-08-04
期刊：
影响因子：
20.3
通讯作者：
Spiekermann, Karsten
中科院分区：
文献类型：
--
作者：
Metzeler, Klaus H.;Herold, Tobias;Spiekermann, Karsten
成人急性髓细胞白血病（AML）中许多最近发现的驱动基因突变的临床和预后相关性尚不明确。我们对德国AML合作组（AMLCG）2项3期试验中664例年龄在18至86岁之间的患者的68个复发突变基因的编码区或热点区域进行了测序。每例患者4个突变的中位数根据细胞遗传学亚组、年龄和既往血液学疾病或化疗史而变化。我们发现模式的显着comutated驱动基因，表明功能协同作用。相反，我们确定了8个几乎不重叠的患者亚组，共占AML患者的78%，这些患者由相互排斥的遗传改变定义。这些亚组可能代表白血病发生的不同潜在途径，显示出截然不同的结果。此外，我们提供了关于基因突变、临床患者特征和这一大型统一治疗AML患者队列的治疗结果之间相关性的详细信息。在包括一系列分子和临床变量的多变量分析中，我们确定DNMT3A和RUNX1突变是AML患者总生存期（OS）较短的重要预测因子。
The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients