title: Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Global hypomethylation of LINE-1 is associated with the progression of and poorer prognosis for MM, possibly due to frequent copy-number loss.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Department of Public Health, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan ; Department of Regional Health Care and Medicine, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ashida
authors.affiliation: Department of Hematology, Hiroshima Red Cross and Atomic-bomb Survivors Hospital, 1-9-6 Senda-cho, Hiroshima 730-8619, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Itagaki
authors.affiliation: Department of Clinical Laboratory, Hiroshima Red Cross and Atomic-bomb Survivors Hospital, 1-9-6 Senda-cho, Naka-ku, Hiroshima 730-8619, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Asaoku
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Public Health, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Mori
authors.affiliation: Division of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura