Epigenetics Meets Genetics in Acute Myeloid Leukemia: Clinical Impact of a Novel Seven-Gene Score
Epigenetics Meets Genetics in Acute Myeloid Leukemia: Clinical Impact of a Novel Seven-Gene Score
复制标题
DOI：
10.1200/jco.2013.50.6337
复制
发表时间：
2014-02-20
影响因子：
45.3
通讯作者：
Bloomfield, Clara D.
中科院分区：
文献类型：
--
作者：
Marcucci, Guido;Yan, Pearlly;Bloomfield, Clara D.
目的急性髓系白血病（AML）的分子危险分层主要基于遗传标记。然而，表观遗传变化，包括DNA甲基化，解除基因表达的调控，也可能具有预后影响。我们评估了整合DNA甲基化和遗传信息在AML.Methods的临床相关性下一代测序分析的甲基化DNA鉴定差异甲基化区域（DMR）与预后突变的老年人（60岁）细胞遗传学正常（CN）AML患者（n = 134）。使用具有启动子DMR和表达水平与结果显著相关的基因来计算预后基因表达加权汇总评分，该评分在四个独立的患者组（n = 355）中进行了测试和验证。（CD 34、RHOC、SCRN 1、F2 RL 1、FAM 92 A1、MIR 155 HG和VWA 8）与启动子DMR和与总生存期相关的表达（OS; P 0.001）。每个基因都有高DMR甲基化和低表达，这与更好的结果相关。计算七种基因表达水平的加权汇总表达评分。低评分与较高的完全缓解（CR）率和较长的无病生存期和OS相关（所有终点P <0.001）。这在多变量模型和两个年轻（< 60岁）和两个老年独立的CN-AML患者组中得到了验证。单独考虑这七个基因，高表达的基因越少，结果越好。没有基因或一个基因高表达的年轻和老年患者有最好的结果（CR率，分别为94%和87%，3年OS，分别为80%和42%）。(C)2013年美国临床肿瘤学会
Purpose Molecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML.Methods Next-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older ( 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355).Results In the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively).Conclusion A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance. (C) 2013 by American Society of Clinical Oncology