Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma.
Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma.
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DOI：
10.1186/gm402
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发表时间：
2012
期刊：
影响因子：
12.3
通讯作者：
Shinomura Y
中科院分区：
文献类型：
--
作者：
Aoki Y;Nojima M;Suzuki H;Yasui H;Maruyama R;Yamamoto E;Ashida M;Itagaki M;Asaoku H;Ikeda H;Hayashi T;Imai K;Mori M;Tokino T;Ishida T;Toyota M;Shinomura Y
本研究的目的是阐明重复元件整体低甲基化在确定多发性骨髓瘤 (MM) 遗传和临床特征中的作用。我们使用四种重复元件（长散布核元件-1 (LINE-1)、Alu Ya5、Alu Yb8 和 Satellite-α）评估了临床样本中的整体甲基化水平，其中包括 74 个 MM 样本和 11 个良性对照样本（7 个意义未定的单克隆丙种球蛋白病 (MGUS) 病例和 4 个正常浆细胞 (NPC) 样本）。我们还使用基于阵列的比较基因组杂交评估了拷贝数改变，并进行了甲基-CpG 结合域测序 (MBD-seq)。重复元件甲基化的整体水平随着浆细胞的恶性程度而下降（NPC>MGUS>MM），并且基因组丢失程度与LINE-1甲基化水平之间存在显着的负相关。我们在常见丢失区域周围确定了 80 个基因组位点作为常见断点 (CBP)，这些位点与 LINE-1 密度增加显着相关。 MBD-seq 分析显示，在 MM 的发展过程中，CBP 位点的平均 DNA 甲基化水平以及 LINE-1 密度较高区域的相对甲基化水平也有所下降。我们证实，各个 LINE-1 位点 5' 非翻译区的甲基化水平与整体 LINE-1 甲基化水平密切相关。最后，LINE-1 低甲基化与较差的总生存率之间存在显着相关性（风险比 2.8，P = 0.015）。 LINE-1 的整体低甲基化与 MM 的进展和较差的预后相关，可能是由于频繁的拷贝数丢失所致。
The aim of this study was to clarify the role of global hypomethylation of repetitive elements in determining the genetic and clinical features of multiple myeloma (MM). We assessed global methylation levels using four repetitive elements (long interspersed nuclear element-1 (LINE-1), Alu Ya5, Alu Yb8, and Satellite-α) in clinical samples comprising 74 MM samples and 11 benign control samples (7 cases of monoclonal gammopathy of undetermined significance (MGUS) and 4 samples of normal plasma cells (NPC)). We also evaluated copy-number alterations using array-based comparative genomic hybridization, and performed methyl-CpG binding domain sequencing (MBD-seq). Global levels of the repetitive-element methylation declined with the degree of malignancy of plasma cells (NPC>MGUS>MM), and there was a significant inverse correlation between the degree of genomic loss and the LINE-1 methylation levels. We identified 80 genomic loci as common breakpoints (CBPs) around commonly lost regions, which were significantly associated with increased LINE-1 densities. MBD-seq analysis revealed that average DNA-methylation levels at the CBP loci and relative methylation levels in regions with higher LINE-1 densities also declined during the development of MM. We confirmed that levels of methylation of the 5' untranslated region of respective LINE-1 loci correlated strongly with global LINE-1 methylation levels. Finally, there was a significant association between LINE-1 hypomethylation and poorer overall survival (hazard ratio 2.8, P = 0.015). Global hypomethylation of LINE-1 is associated with the progression of and poorer prognosis for MM, possibly due to frequent copy-number loss.
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影响因子：
6.4
作者：
Daskalos, Alexandros;Nikolaidis, Georgios;Liloglou, Triantafillos
通讯作者：
Liloglou, Triantafillos
影响因子：
20.3
作者：
Martinez-Garcia, Eva;Popovic, Relja;Licht, Jonathan D.
通讯作者：
Licht, Jonathan D.
影响因子：
20.3
作者：
Avet-Loiseau, H;Facon, T;Bataille, R
通讯作者：
Bataille, R
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
3.5
作者：
Jiang Y;Lucas I;Young DJ;Davis EM;Karrison T;Rest JS;Le Beau MM
通讯作者：
Le Beau MM