Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia
Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia
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DOI：
10.1056/nejmoa031046
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发表时间：
2004-04-15
影响因子：
158.5
通讯作者：
Pollack, JR
中科院分区：
文献类型：
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作者：
Bullinger, L;Döhner, K;Pollack, JR
背景：在急性髓系白血病(AML)患者中，复发性细胞遗传学异常的存在与否被用来确定合适的治疗方法。然而，目前的分类系统不能完全反映疾病的分子异质性，治疗分层困难，特别是对于核型正常的中危AML患者。方法：采用互补DNA微阵列技术检测116例成人AML患者(其中45例核型正常)外周血或骨髓标本中基因表达水平。我们使用非监督层次聚类分析来识别具有不同基因表达特征的分子亚群。使用59名患者的样本训练集，我们应用一种新的监督学习算法来设计基于基因表达的临床结果预测因子，然后使用由其余57名患者组成的独立验证组进行测试。结果：非监督分析发现了新的AML分子亚型，包括两个具有正常核型的AML预后相关亚群。使用监督学习算法，我们构建了一个最优的133基因临床结局预测因子，它准确地预测了独立验证组(P=0.006)患者的总存活率(P=0.006)，包括核型正常的急性髓细胞白血病患者亚组(P=0.046)。在多因素分析中，基因表达预测因素是一个较强的独立预后因素(优势比，8.8；95%可信区间，2.6~29.3；P
Background: In patients with acute myeloid leukemia (AML), the presence or absence of recurrent cytogenetic aberrations is used to identify the appropriate therapy. However, the current classification system does not fully reflect the molecular heterogeneity of the disease, and treatment stratification is difficult, especially for patients with intermediate-risk AML with a normal karyotype.Methods: We used complementary-DNA microarrays to determine the levels of gene expression in peripheral-blood samples or bone marrow samples from 116 adults with AML (including 45 with a normal karyotype). We used unsupervised hierarchical clustering analysis to identify molecular subgroups with distinct gene-expression signatures. Using a training set of samples from 59 patients, we applied a novel supervised learning algorithm to devise a gene-expression-based clinical-outcome predictor, which we then tested using an independent validation group comprising the 57 remaining patients.Results: Unsupervised analysis identified new molecular subtypes of AML, including two prognostically relevant subgroups in AML with a normal karyotype. Using the supervised learning algorithm, we constructed an optimal 133-gene clinical-outcome predictor, which accurately predicted overall survival among patients in the independent validation group (P=0.006), including the subgroup of patients with AML with a normal karyotype (P=0.046). In multivariate analysis, the gene-expression predictor was a strong independent prognostic factor (odds ratio, 8.8; 95 percent confidence interval, 2.6 to 29.3; P