DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes
DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes
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DOI：
10.1200/jco.2009.23.4781
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发表时间：
2010-02-01
影响因子：
45.3
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
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作者：
Shen, Lanlan;Kantarjian, Hagop;Issa, Jean-Pierre J.
目的目前的骨髓增生异常综合征(MDS)分类系统，包括国际预后评分系统(IPSS)，不能完全反映疾病的分子异质性。分子特征可以预测临床结果，并帮助患者分层进行靶向治疗。使用DNA去甲基化药物地西他滨的表观遗传疗法对MDS的治疗是临床有效的。我们对24例MDS患者进行了24个基因启动子CpG岛甲基化的筛查，发现有10个基因发生异常甲基化。然后，我们对来自三个独立研究的317名患者样本进行了甲基化定量分析，并评估了甲基化与临床结果的关系。结果在89名MDS患者的初始训练队列中，单个基因的甲基化频率从7%到70%，并且高度一致。因此，我们根据每个患者的所有基因定义了甲基化z分数。我们发现，与甲基化水平较低的患者相比，甲基化水平较高的患者的中位总生存期(分别为12.3个月和17.5个月；P=0.04)和较短的中位无进展生存期(分别为6.4个月和14.9个月；P=0.009)。该甲基化预后模型与年龄、性别和IPSS组无关。应用于两个验证队列(228名患者)，该模型被确认为一个独立的预后预测因子。虽然基线水平的甲基化与临床对地西他滨的反应无关，但我们观察到随着时间的推移甲基化减少与临床反应显著相关。结论DNA甲基化可以预测MDS的总体和无进展生存率。
PurposeThe current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS.Patients and MethodsWe screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome.ResultsIn an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses.ConclusionDNA methylation predicts overall and progression-free survival in MDS.