First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.
Department of Public Health, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
Genome Med. 2012 Dec 22;4(12):101. doi: 10.1186/gm402. eCollection 2012.
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.
本研究旨在阐明重复元件的整体低甲基化在确定多发性骨髓瘤（MM）的遗传和临床特征中的作用。
我们在包括 74 例 MM 样本和 11 例良性对照样本（7 例单克隆丙种球蛋白病不明意义（MGUS）和 4 例正常浆细胞（NPC））的临床样本中使用四个重复元件（长散布核元件-1（LINE-1）、Alu Ya5、Alu Yb8 和卫星-α）评估整体甲基化水平。我们还使用基于阵列的比较基因组杂交进行拷贝数改变评估，并进行甲基-CpG 结合域测序（MBD-seq）。
重复元件的整体甲基化水平随浆细胞恶性程度的降低而降低（NPC>MGUS>MM），并且基因组丢失程度与 LINE-1 甲基化水平呈显著负相关。我们鉴定了 80 个基因组位点作为常见断裂点（CBPs），位于常见缺失区域周围，与 LINE-1 密度的增加显著相关。MBD-seq 分析显示，在 MM 发展过程中，CBPs 位点的平均 DNA 甲基化水平和高 LINE-1 密度区域的相对甲基化水平也降低。我们证实了相应 LINE-1 基因座的 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 低甲基化与总体生存率较差之间存在显著相关性（风险比 2.8，P=0.015）。
LINE-1 的整体低甲基化与 MM 的进展和预后较差相关，可能是由于频繁的拷贝数丢失所致。
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