弥漫性大B细胞淋巴瘤中的表观基因组进化
Epigenomic evolution in diffuse large B-cell lymphomas.
作者信息
Pan Heng, Jiang Yanwen, Boi Michela, Tabbò Fabrizio, Redmond David, Nie Kui, Ladetto Marco, Chiappella Annalisa, Cerchietti Leandro, Shaknovich Rita, Melnick Ari M, Inghirami Giorgio G, Tam Wayne, Elemento Olivier
机构信息
1] Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [2] Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
1] Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [2] Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [3] Hematology/Oncology Division, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
出版信息
Nat Commun. 2015 Apr 20;6:6921. doi: 10.1038/ncomms7921.
The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-β (TGF-β) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.
表观基因组改变对肿瘤进展和复发的作用尚未得到充分表征。在此，我们阐述弥漫性大B细胞淋巴瘤（DLBCL）中疾病进展与DNA甲基化之间的关联。通过对13对DLBCL诊断-复发样本对进行单碱基对分辨率的全基因组DNA甲基化分析，我们发现DLBCL患者在复发期间肿瘤甲基化组呈现异质性演变。我们鉴定出差异甲基化的调控元件，并确定了一个与复发相关的甲基化特征，该特征汇聚于关键信号通路，如转化生长因子-β（TGF-β）受体活性。我们还观察到从诊断到复发肿瘤样本，肿瘤内甲基化异质性降低。在一个独立验证队列中，无复发生存的患者在诊断时的肿瘤内甲基化异质性低于复发患者。此外，肿瘤内甲基化异质性可预测复发时间。因此，我们提出表观基因组异质性可能支持或驱动复发表型，并可用于预测DLBCL复发。
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