Overview of Myeloma Genetics
Myeloma develops as the consequence of a multistep process during which plasma cells accumulate a series of genetic hits that result in a selective advantage for the clone. The earliest recognizable stage of this process is monoclonal gammopathy of undetermined significance (MGUS), followed by asymptomatic or smoldering myeloma, symptomatic myeloma requiring treatment (or multiple myeloma [MM]) and finally plasma cell leukemia (PCL). Myeloma is usually preceded by an age-dependent premalignancy called MGUS, which is present in >5% of adults over the age of 70 years. MGUS is asymptomatic and is characterized by a small clonal population of plasma cells that produce a monoclonal protein but cause no end-organ damage. Additional genetic events are required for this condition to progress to myeloma, and this progression risk has been quantified at 1% per year. Smoldering myeloma is distinguished from MGUS by having a greater intramedullary tumor-cell content (>10%), while in MM, the malignant clone causes clinically relevant sequalae such as lytic bone lesions, renal impairment or bone-marrow failure. PCL represents an aggressive entity in which the plasma cells are able to exist outside the protective niche of the bone marrow microenvironment. This multistep process provides a framework within which causative genetic events of myeloma can be studied, as lesions can be studied at the various stages of disease (Figure 1).
Genetic events in myeloma pathogenesis.
IGH: Immunoglobulin heavy; MGUS: Monoclonal gammopathy of undetermined significance.
Genetically, MM can be classified roughly into two groups characterized by hyperdiploidy and nonhyperdiploidy. Hyperdiploidy in myeloma has a specific genotype involving trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. The nonhyperdiploid group is characterized by frequent translocations of the immunoglobulin heavy chain alleles (IGH@) at 14q32 and partner chromosomes that include chromosomes 4, 6, 11, 16 and 20 recurrently. In a number of instances, the partner chromosome remains unknown. Translocation events bring the partner oncogenes under the influence of the IGH@ promoter/enhancer region, resulting in upregulation of the juxtaposed gene. Hyperdiploidy and IGH@ translocations are thought to represent primary genetic events in the framework of myeloma pathogenesis, as they are found at similar frequencies in MGUS as in myeloma. Interestingly, IGH@ translocations are found more frequently in female myeloma patients, while hyperdiploidy is more common in male patients, although the reasons underlying this are not understood.
Further genetic events such as copy number abnormalities, mutations and epigenetic modifiers occur in both MGUS and myeloma and are required for progression to a malignant phenotype. Gene mapping has identified del(1p), +1q, del(6q), del(8p), del(12p), del(13q), del(14q), del(16q) and del(17p) as being recurrent genetic events in myeloma and several of these lesions have been linked with clinical outcome.[4–6] In addition to structural DNA changes, changes to epigenetic regulation mediated via DNA methylation or histone modification have also been shown to be associated with disease progression.
Expert Rev Hematol. 2012;5(6):603-617. © 2012 Expert Reviews Ltd.