Etiology

The etiology of monoclonal gammopathies remains unknown. The mechanisms underlying the clonal evolution of plasma cells are the focus of intense clinical and laboratory investigations. The epidemiologic characteristics of the disease suggest possible predisposing conditions. Various factors, including environmental, genetic, infectious, and inflammatory causes have been hypothesized; however, definitive evidence for one or more of these is lacking.

Genetic predisposition

  • There is an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) among the black population in the US, which is similar to that reported in population-based studies from Ghana.[24] Family studies of patients with myeloma and MGUS have demonstrated an increased prevalence of monoclonal gammopathies among first-degree relatives.[25]

Environmental factors

  • There is an increased prevalence of myeloma and MGUS among survivors of atomic bombs, those exposed to radiation, and those with increased exposure to chemicals such as pesticides and petroleum products.[27][28][29][30]

Infectious etiology

  • In myeloma studies, human herpes virus genetic sequences have been identified in the clonal plasma cells or in the cells in the marrow microenvironment.[31]

Autoimmune conditions

  • The association of monoclonal proteins with autoimmune conditions suggests that aberrant immune response processes may have a role in the development of the monoclonal protein. However, it is unclear whether this is driven by a limited number of antigens or if it is an antigen-independent process.

Genetic abnormalities

Significant progress has been made in deciphering the underlying genetic changes in the context of MGUS and myeloma.[32][33] Given the low proliferative nature of the plasma cells in these disorders, conventional assessments of genetic abnormalities using metaphase genetics have been insufficient.

Fluorescence in situ hybridization (FISH) and more sophisticated techniques, such as gene expression profiling (GEP) and array comparative genomic hybridization (aCGH), have provided an insight into the genetic etiology of the disease.[34][35][36] Monoclonal plasma cells in MGUS and myeloma have numerical and structural abnormalities in their chromosomes. The numerical abnormalities typically take the form of increased copies of odd-numbered chromosomes, typically referred to as a hyperdiploid picture, or partial or complete loss of certain chromosomes such as chromosomes 1, 13, 14, and 17. In addition, amplification of certain regions within a chromosome can be found as with chromosome 1q amplification. The structural abnormalities typically consist of translocations involving the immunoglobulin heavy chain locus on chromosome 14 with several other partner chromosomes (chromosomes 4, 6, 11, 16, 20) or deletions involving chromosomes 1, 5, or 17. The discovery of genetic changes in the monoclonal plasma cells has increased the possibility of acquired genetic abnormalities as a driving force behind the origin and the subsequent progression of the disease. Studies using advanced genomic techniques have led to the identification of recurrent mutations and other structural and numerical abnormalities involving a variety of genes.[37][38]

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