Distinguishing primary and secondary translocations in multiple myeloma

Abstract

Multiple myeloma (MM) is a malignant post-germinal center tumor of somatically-mutated, isotype-switched plasma cells that accumulate in the bone marrow. It often is preceded by a stable pre-malignant tumor called monoclonal gammopathy of undetermined significance (MGUS), which can sporadically progress to MM. Five recurrent primary translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 have been identified in MGUS and MM tumors. The five partner loci include 11q13, 6p21, 4p16, 16q23, and 20q12, with corresponding dysregulation of CYCLIN D1, CYCLIN D3, FGFR3/MMSET, c-MAF, and MAFB, respectively, by strong enhancers in the IgH locus. The five recurrent translocations, which are present in 40% of MM tumors, typically are simple reciprocal translocations, mostly having breakpoints within or near IgH switch regions but sometimes within or near VDJ or JH sequences. It is thought that these translocations are caused by aberrant IgH switch recombination, and possibly by aberrant somatic hypermutation in germinal center B cells, thus providing an early and perhaps initiating event in transformation. A MYC gene is dysregulated by complex translocations and insertions as a very late event during the progression of MM tumors. Since the IgH switch recombination and somatic hypermutation mechanism are turned off in plasma cells and plasma cell tumors, the MYC rearrangements are thought to be mediated by unknown mechanisms that contribute to structural genomic instability in all kinds of tumors. These rearrangements, which often but not always juxtapose MYC near one of the strong immunoglobulin enhancers, provide a paradigm for secondary translocations. It is hypothesized that secondary translocations not involving a MYC gene can occur at any stage of tumorigenesis, including in pre-malignant MGUS tumor cells.