Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

Abstract

Cytogenetic studies in clonal plasma cell disorders have mainly been done in whole bone marrow or CD138 + microbead-enriched plasma cells and suggest that recurrent immunoglobulin heavy chain translocations -e.g. t(4;14) -are primary oncogenetic events. The aim of this study was to determine cytogenetic patterns of highly purified aberrant plasma cells (median purity ≥98%) in different clonal plasma cell disorders. We analyzed aberrant plasma cells from 208 patients with multiple myeloma (n=148) and monoclonal gammopathy of undetermined significance (n=60) for the presence of del(13q14), del(17p13) and t(14q32) using multicolor interphase fluorescence in situ hybridization. Additionally, immunoglobulin heavy chain gene arrangements were analyzed and complementarity determining region 3 was sequenced in a subset of patients and combined multicolor interphase fluorescence in situ hybridization/immunofluorescent protein staining analyses were performed in selected cases to confirm clonality and cytogenetic findings. At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy. The cytogenetic heterogeneity of individual cases reflected coexistence of cytogenetically-defined aberrant plasma cell clones, and led to the assumption that karyotypic alterations were acquired stepwise. Cases of multiple myeloma and monoclonal gammopathy of undetermined significance frequently showed different but related cytogenetic profiles when other cytogenetic alterations such as deletions/gains of the immunoglobulin heavy chain or the fibroblast growth factor receptor 3 were additionally considered. Interestingly, in 24% of multiple myeloma versus 62% of monoclonal gammopathy of undetermined significance patients with an immunoglobulin heavy chain translocation, aberrant plasma cells with and without t(14q32) coexisted in the same patient. Our data suggest that recurrent immunoglobulin heavy chain translocations might be absent in the primordial plasma cell clone in a significant proportion of patients with clonal plasma cell disorders carrying these cytogenetic alterations.

Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance

“…Although clonal heterogeneity at diagnosis and clonal tiding from diagnosis to patients' relapse has been recently described, [15][16][17]21,33 no attention has been paid to primary chemoresistant PCs that persist even among patients in serologic response (ie, MRD). Because persistence of MRD is strongly linked to an inferior survival, 4-7 a better understanding of MRD clonal PCs is warranted to potentially overcome their chemoresistant phenotype.…”

Circulating clonotypic B cells in multiple myeloma and monoclonal gammopathy of undetermined significance

“…IGH-FGFR3, IGH-MMSET) expressed by CD138 + M-PC. [6][7][8] Moreover, intraclonal heterogeneity, as assessed through the analysis of the IGHV gene sequence 9 or through the investigation of cytogenetic alterations 10 and gene mutations evaluated by whole exome sequencing, 11 has been reported within the M-PC population, suggesting that the tumor PC compartment could be continuously repopulated by more than one stem cell.…”

B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

“…94,95 It has been proposed that other secondary alterations can occur as this tumor progresses, including somatic mutations like those known to activate the RAS family of monomeric GTPases (24-50% of MMs) and the acquisition of t8q24 (50% of advanced MMs), which increases MYC expression.…”

“…94,95 It has been proposed that other secondary alterations can occur as this tumor progresses, including somatic mutations like those known to activate the RAS family of monomeric GTPases (24-50% of MMs) and the acquisition of t8q24 (50% of advanced MMs), which increases MYC expression. 96,97 RAS downstream signaling also seems to be central to the pathogenesis of MM, since RAS itself and other downstream RAS effectors (i.e.…”