Array CGH analysis of multiple myeloma (MM) and MGUS, Sapporo and Hiroshima samples. Homo sapiens

Multiple myeloma (MM) is a malignant plasma cell tumor characterized by various chromosomal aberrations. From the aspect of epigenetics, hypomethylation of DNA repetitive elements has been considered to induce chromosomal instability. We therefore have been interested in how it is related to chromosomal aberrations in MM. To address this, methylation levels of repetitive elements (including LINE-1, Alu and Satellite-alpha) and copy number alterations were measured in clinical samples (N=85). Bisulfite-pyrosequencing (N=85) and array-based comparative genomic hybridization (N=73) were used for these measurement, respectively. As results, methylation levels of repetitive elements were linearly associated with the degree of malignancy of plasma cells. Combined with hierarchical clustering of the result of aCGH, hypomethylation of repetitive elements was well associated with frequent chromosomal deletions. In particular, methylation levels of LINE-1 was significantly higher in samples with chromosome 13 deletion than the other (36.1% vs. 44.0%, P=0.010). The number of deleted probes was significantly correlated with LINE-1 methylation levels (R=-0.531). Finally, we observed significantly poorer prognosis in the lower LINE-1 methylation group (HR=2.8, P=0.015, compared to the higher methylation group). In conclusion, DNA methylation levels of repetitive elements, especially of LINE-1, are associated with the frequency of chromosomal deletions and prognosis in MM. Overall design: 67 MM samples and 6 monoclonal gammopathy of undetermined significance (MGUS) samples were analyzed, all samples were selected by CD138 sorting