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KOS 2007: Chromosomal and epigenetic abnormalities in MGUS and MM Post-MGUS
Johannes Drach, MD
Medical University of Vienna
Department of Medicine I
Clinical Division of Oncology
Vienna, Austria

NOTE: Although the IMF did not receive permission to post either the slides or audio of this presentation, we are bringing you a summary by our medical writer, Lynne Lederman, PhD.

AUTHORS:J. Drach, H. Kaufmann, J. Ackermann, G. Heller, S. Seidl, S. Zöchbauer-Müller
Medical University of Vienna, Department of Medicine I, Clinical Division of Oncology; Vienna, Austria

It is not clear whether myeloma that develops after MGUS is identical to myeloma with an unknown prior history. Genetic abnormalities associated with myeloma can be detected in MGUS, and although some of these are associated with poor prognosis in myeloma, they are also associated with MGUS that is stable for years. Dr. Drach proposed that post-MGUS myeloma appears to be a separate entity with a different outcome than myeloma with an unknown prior history. Those patients with post-MGUS MM with only deletion 13 had a much better survival, and those with t(11;14) a much poorer survival. His group is looking at epigenetic changes in plasma cells that might be associated with development of myeloma, e.g., aberrant methylation of promoter regions in tumor suppressor genes. Demethylating agents such as 5-aza-2-deoxycytidine and/or trichostatin A were used to treat cell lines, and about 470 unique genes were induced in at least one of the lines. Of these, 88% were shown to have CpG islands, and therefore to be genuine methylation targets. Although all chromosomes contained some of these genes, an obvious cluster occurred on chromosome 6 at 6p21. This process selected some genes that have previously been identified in other cancers that were not previously known to be associated with myeloma, including genes involved in the cell cycle, cell adhesion, signaling, and DNA repair. Methylation was higher in an analysis of DNA from 111 patients with myeloma than from 25 patients with MGUS. Methylation seems to be associated with poorer outcome. Analysis of proteins using gel electrophoresis followed by nanoflow liquid chromatography revealed some potentially important methylation targets that might be useful in predicting response, including apoptosis-inducing factor 1, several cell adhesion molecules, serine/threonine protein kinase, adenosine deaminase, estradiol 17-beta dehydrogenase, and NF-κB inhibitory interacting ras-like protein 2.

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