Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma

We assessed global methylation levels using four repetitive elements (LINE-1, Alu Ya5, Alu Yb8, and Satellite-alpha) in clinical samples that included 74 cases of MM and 11 benign controls consisting of 7 cases of monoclonal gammopathy of undetermined significance (MGUS) and 4 samples of normal plasma cells (NPCs). We also evaluated copy number alterations using array-based comparative genomic hybridization (aCGH) 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 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 decline during the development of MM. We confirmed that levels of methylation of the 5' UTR of respective LINE-1 loci correlated strongly with global LINE-1 methylation levels. Finally, there was a significant association between LINE-1 hypomethylation and a poorer overall survival (hazard ratio = 2.8, P = 0.015).Global hypomethylation of LINE-1 is associated with the progression and a poor prognosis in MM, possibly due to frequent copy number loss.