The Molecular Cytogenetic Analysis of MGUS Provides Additional Evidence for a Novel, 14q-Translocation Independent Pathogenetic Pathway in Clonal Plasma Cell Disorders.

Introduction: There is growing evidence for two almost mutually exclusive pathways in the pathogenesis of multiple myeloma (MM): the first one is characterized by the activation of oncogenes through one of five "primary" IgH translocations, while the second one seems to be designated by the presence of various chromosomal extra copies ("hyperdiploidy") in the absence of a primary 14q-translocation. However, the pivotal chromosomal gains in hyperdiploid tumors and the crucial genetic events in the transition of MGUS to overt MM are unknown.

Aims: i) to evaluate the incidences of chromosomal aberrations using a myeloma-specific DNA probe in pts. with MGUS ii) to compare the FISH data from the present MGUS series with our MM FISH data previously determined on a large series of tumors with the goal to distinguish primary aberrations (already present in MGUS and therefore potentially involved in the process of immortalization) and secondary genetic changes (not or infrequently detectable in MGUS but common in MM, therefore potentially participating in the process of MGUS-MM transition).

Material and Methods: Bone marrow aspirates from 50 pts. diagnosed with MGUS were obtained during routine diagnostic procedures. In the majority of cases, a positive selection of plasma cells using immunomagnetic beads (CD 138) was performed. FISH was combined with immunocytology using light-chain fluorescence antibodies for precise detection of plasma cells carrying the respective clonal light chain (kappa or lambda). At least 50 to 100 plasma cells were evaluated for each probe. The DNA probe set comprised probes mapping to chromosome bands 1p22, 1q21, 6q21, 8p11, 9q34, 11q25, 13q14, 14q32, 17p13, and 22q11.

Results: The most frequent chromosomal aberrations in our MGUS series were (in order of decreasing prevalence; + denotes gains, mostly trisomies, - denotes losses, mostly deletions): t(14q32)/46%, +9q/35%, +11q/27%, +1q/25%, and 13q-/19%. The incidences of all other aberrations were lower than 8%. Comparing the incidences of aberrations in MM and MGUS, the greatest difference was found for 13q- (43% vs. 19%), while it was <15% for all other abnormalities. Of note, 22q- was present in 13% of cases with MM, while no pt. with MGUS exhibited this abnormality.

Conclusions: i) The high incidence of +9q and +11q in MGUS suggests these chromosomal extra copies as early genetic events and provides further evidence for a novel, 14q-translocation independent pathogenetic pathway in clonal plasma cell disorders. ii) Our data indicate that 13q- and 22q- could be relevant for the transition of MGUS to MM. iii) +1q, previously proposed as a marker of advanced MM, is already detectable in 25% of pts. with MGUS.