DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features
DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features
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DOI：
10.1182/blood-2014-08-596247
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发表时间：
2015-03-19
期刊：
影响因子：
20.3
通讯作者：
Bertoni, Francesco
中科院分区：
文献类型：
--
作者：
Arribas, Alberto J.;Rinaldi, Andrea;Bertoni, Francesco
脾边缘区淋巴瘤是一种罕见的淋巴瘤。 7q31 缺失和影响 NOTCH2 和 KLF2 基因的体细胞突变是最常见的基因组畸变。表观遗传变化可以通过药理学恢复；因此，鉴定具有特定表观基因组改变的患者群体可能具有治疗相关性。在这里，我们将全基因组 DNA 启动子甲基化分析与基因表达分析以及临床和生物学变量相结合。对 98 个样本的测试系列进行无监督聚类分析，确定了 2 个具有不同启动子甲基化程度的簇。与较低 (Low-M) 簇相比，包含具有较高启动子甲基化 (High-M) 的样本的簇的总体存活率较差。 High-M 表型的预后相关性在 36 名患者的独立验证集中得到了证实。在整个系列中，High-M表型与IGHV1-02的使用、NOTCH2基因突变、7q31-32缺失和组织学转化相关。在 High-M 组中，许多肿瘤抑制基因被甲基化并受到抑制。 PRC2 亚基基因和几个促生存淋巴瘤基因未甲基化并过度表达。基于 3 个基因（CACNB2、HTRA1、KLF4）甲基化的模型确定了结果较差的患者子集。将脾边缘区淋巴瘤细胞系暴露于去甲基化剂导致 High-M 表型部分逆转并抑制增殖。
Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation.