Specialized Program of Research Excellence in Myeloma (SPORE)

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are pre-malignant stages of the plasma cell (PC) neoplasm multiple myeloma (MM). Multiple chromosomal and genetic abnormalities have been described in MGUS, SMM and MM, and are thought to be important for disease pathogenesis and disease progression. We need to understand

  • What genomic abnormalities place a patient with MGUS/SMM at high risk of progression to MM?
  • Which genetic loci may be lost or gained in association with evolution to MM?

Hypothesis 1 Genetic and chromosomal abnormalities present in the PCs of MGUS/SMM patients, at diagnosis, result in different risks of progression to MM. Other biologic and prognostic markers such as the PC labeling index (PCLI), bone marrow (BM) plasmacytosis, β2-microglobulin and concentration of the monoclonal protein are likely higher in those MGUS patients with abnormalities that put them at higher risk of disease progression. We will test MGUS samples for the most important translocations (+14q32, t(4;14)(p16.3;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), IgL-λ-light chain translocations (+22q11) and deletions (chromosome 13 monosomy, and 17p13). (See FISH images) We will also test the samples for K/N Ras mutations, and methylation of p16.

Hypothesis 2 Chromosomal regions of recurrent gain and loss harbor genes, activation or inactivation of which is responsible, for the progression through the different stages of the PC disorders. The genome wide search for these regional alterations, and ultimately identification of the targets of such alterations will yield clues into the specific mechanisms leading to MGUS/SMM and MM. Thus we wish to generate a comprehensive genome-wide profile of regional gains and losses in MGUS and MM to identify candidate loci relevant to genesis, progression and prognosis, using array based comparative genomic hybridization.

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