Guido Marcucci, Pearlly Yan, Kati Maharry, David Frankhouser, Deedra Nicolet, Klaus H. Metzeler, Jessica Kohlschmidt, Krzysztof Mrózek, Yue-Zhong Wu, Donna Bucci, John P. Curfman, Susan P. Whitman, Ann-Kathrin Eisfeld, Jason H. Mendler, Sebastian Schwind, Heiko Becker, John C. Byrd, Ramiro Garzon, Michael A. Caligiuri, Stefano Volinia, and Clara D. Bloomfield, The Ohio State University Comprehensive Cancer Center; Ralf Bundschuh, The Ohio State University, Columbus, OH; Kati Maharry, Deedra Nicolet, and Jessica Kohlschmidt, Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Maria R. Baer, Greenebaum Cancer Center, University of Maryland, Baltimore, MD; Meir Wetzler, Roswell Park Cancer Institute, Buffalo; Jonathan E. Kolitz, Monter Cancer Center, Lake Success, NY; Thomas H. Carter, University of Iowa, Iowa City, IA; Bayard L. Powell, The Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC; Richard M. Stone, Dana-Farber Cancer Institute, Boston, MA; Constance Bär and Christoph Plass, German Cancer Research Center, Heidelberg, Germany.
J Clin Oncol. 2014 Feb 20;32(6):548-56. doi: 10.1200/JCO.2013.50.6337. Epub 2013 Dec 30.
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.
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).
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).
A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.
急性髓系白血病（AML）的分子风险分层主要基于遗传标志物。然而，表观遗传变化，包括 DNA 甲基化，会导致基因表达失调，也可能具有预后影响。我们评估了整合 AML 中 DNA 甲基化和遗传信息的临床相关性。
对年龄较大（≥60 岁）、细胞遗传学正常（CN）的 AML 患者（n=134）中与预后突变相关的甲基化 DNA 的下一代测序分析确定了差异甲基化区域（DMR）。与预后显著相关的具有启动子 DMR 和表达水平的基因被用于计算预后基因表达加权综合评分，该评分在四个独立的患者组（n=355）中进行了测试和验证。
在训练集中，我们确定了七个具有启动子 DMR 和与总生存期（OS）相关的表达的基因（CD34、RHOC、SCRN1、F2RL1、FAM92A1、MIR155HG 和 VWA8）（P≤0.001）。每个基因都具有高 DMR 甲基化和低表达，与更好的预后相关。计算了七个基因表达水平的加权综合表达评分。低评分与更高的完全缓解（CR）率、更长的无病生存和 OS 相关（所有终点 P＜0.001）。这在多变量模型和两个年轻（＜60 岁）和两个年长的 CN-AML 独立患者组中得到了验证。考虑到七个基因单独作用，具有高表达的基因越少，结果越好。没有基因或只有一个基因具有高表达的年轻和年长患者的结局最好（CR 率分别为 94%和 87%；3 年 OS 率分别为 80%和 42%）。
包含表观遗传和遗传预后信息的七个基因评分确定了具有治疗指导意义的新型 AML 亚组。
