Abstract
Introduction: Aberrations involving immunoglobulin genes (Ig) are recurrent in Multiple Myeloma (MM) and carry prognostic significance. One of them, the t(14;20) (q32;q12) leading to overexpression of the transcription factor MAFB has been identified in myeloma cell lines, rarely in MM, and never in MGUS. The clinical significance of this cryptic aberration remains poorly unknown. The aim of the present study was to assess the frequency and prognostic value of this chromosomal change.
Materials and Methods: A series of 1200 samples from patients with MM or MGUS were assessed by interphase FISH either on immunologically identified kappa/lambda positive plasmacells (I-FISH) or on CD138 purified plasmacells (PCs). Cases selected were consecutive cases sent for routine cytogenetic analysis in which a translocation involving Ig was demonstrated by FISH (split signal with the Breakapart probe, Abbott) and was shown to be distinct from t(11;14), t(4;14), t(14;16) and t(6;14) (using specific probes), respectively. A double color interphase FISH assay was applied for the detection of the t(14;20), using a set of BAC probes located on 20q11-q12: RP4-616B8 and RP3-404H4 (centromeric to MAFB, labelled in Spectrum Orange) and RP4-644L1 and RP1-94E24 (telomeric to MAFB, labelled in Spectrum Green).
Results: A characteristic split signal, was observed in 10 patients (0.8%), 8 females and 2 males, aged 49–83 years (median 69). All but 2 of them suffered from MM in advanced stage (Durie and Salmon stage II in 2 and stage III in 6 patients) and displayed multiple bone lesions. The light chain isotype was kappa in 4, lambda in 3, unknown in 1. Two cases were non secreting (but showed kappa intracytoplasmic expression). The heavy chain isotype was IgG in 6, and IgA in 1. Therapy was required in all but 1 case (1 line in 1, 2 lines in 3, and 3 lines in 5 patients, respectively). The front line consisted of VAD (n=5) followed by high dose Melphalan and autologous stem cell transplantation (ASCT)(n=4), among these, 1 had a double AST and one had a reduced intensity conditioning regimen allogeneic transplantation), Melphalan-Prednisone (MP) (n=1) and MP+Thalidomide or Lenalidomide or Bortezomib (n=3). All but 1 cases treated with VAD showed response (at least PR) which persisted at least transiently after high dose therapy (2 cases relapsed after achieving response). Two patients treated upfront with MP associated with one of the new drugs responded to this regimen. The patient treated with MP alone did not respond, was subsequently refractory to Thalidomide+Dexamethasone, but responded to Bortezomib. After a median follow-up period of 10,5 months (range 1 months – 10 years), 7 patients are alive (1 with progressive disease) and 3 died because of progressive disease, 2, 19 and 120 months after diagnosis, respectively. Conventional cytogenetic analysis showed clonal aberrations in 2 cases (hypodiploid karyotypes with complex changes). FISH analysis showed a balanced t(14;20) in all cases. The second IgH allele was intact in 9 patients and was involved (subclonally) in a t(7;14)(q31;q32) in 1 patient. Associated changes were: loss of 13q in 8, and loss of 17p13 in 1 cases. In conclusion, the t(14;20)(q32;q12) is a rare change in MM, and is associated with hypodiploidy (i.e. loss of 13q), advanced stage and poor outcome.
Features of chromosomal abnormalities in spontaneous abortion cell culture failures detected by interphase FISH analysis
