High frequencies of chromosomal aberrations in multiple myeloma and monoclonal gammopathy of undetermined significance in direct chromosome preparation

Abstract

SummaryAlthough many cases of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are cytogenetically normal, interphase fluorescence in situ hybridization (FISH) analyses reveal aberrations in the majority of the cases. Most likely, non-neoplastic cells are more prone to divide in culture than neoplastic cells. Direct chromosome preparations (DCP) would be one way to circumvent this methodological problem. We have investigated 47 bone marrow samples from 39 patients by DCP. A median of 58 metaphases (range 9-158) was analysed per sample. Interphase FISH analyses using probes to detect IGH rearrangements, -13/13q-, +3, +7, and +11 were also performed. Abnormal karyotypes were detected in 15 (63%) of 24 MM and in 4 (50%) of eight MGUS/smouldering MM (SMM) cases that could be successfully cytogenetically analysed. Age, sex, or degree of bone marrow plasma cell (PC) infiltration did not influence the karyotypic patterns (P > 0AE05). However, the frequencies of aberrant karyotypes varied in relation to the Colcemide concentrations used -7% (30 ng/ml) versus 69% and 67% (100 and 200 ng/ml, respectively) (P ¼ 0AE01). Combining the G-banding and FISH results, abnormalities were detected in 29 of 31 (94%) MM and in six of eight (75%) MGUS/SMM patients. Thus, cytogenetic and FISH analyses after DCP using 100-200 ng Colcemide/ml identified aberrations in most MM/MGUS/SMM, irrespective of PC percentages.

Dysfunctional homologous recombination mediates genomic instability and progression in myeloma

“…1,9,16,17,[20][21][22][23][24][25] In this study, we used multiple myeloma (MM) as a model cancer to evaluate the molecular mechanisms of acquisition of genetic instability and progression of cancer because significant chromosomal instability is observed in this malignancy, with more than 11 cytogenetic abnormalities observed per karyotype and with demonstrated progressive cytogenetic change over time in patient samples and in myeloma-derived cell lines. [26][27][28] Here we report that HR activity is constitutively elevated in MM cell lines and patient samples and demonstrate that the inhibition of HR activity leads to a significant reduction in the acquisition of new genetic changes whereas induction of HR activity leads to significant elevation in the number of new mutations over time and development of drug resistance in MM cells. [29][30][31][32] and were maintained in a state of logarithmic growth.…”

Hyperdiploidy Is a Common Finding in Monoclonal Gammopathy of Undetermined Significance and Monosomy 13 Is Restricted to These Hyperdiploid Patients

“…Several studies have suggested that IgH translocations might occur early in the development of monoclonal gammopathies, possibly as an immortalizing event, rather than related to transition to MM (9 -11, 18, 20 -22). There is still matter of debate whether D13 is an initiation event or is related to transition to MM due to the variable percentage of MGUS patients displaying that anomaly in literature data (9, 10, 18 -23 Thus far, little is known about the real incidence of hyperdiploidy and hypodiploidy in MGUS due to inability to do conventional cytogenetic study in most instances (14,15). Flow cytometry (FCM), a good method to ascertain hyperdiploidy in MM patients (24 -27), was applied to MGUS patients and, although the number of cases reported was low, showed that some patients showed a hyperdiploid PC clone (24 -26, 28, 29).…”

“…Occurrence of D13 in hypodiploid MGUS might be a late event, possibly related to transition to MM. However, we cannot exclude that hypodiploidy is rare in MGUS because hypodiploid MM originates rarely from a preceding MGUS condition.IgH rearrangements account for up to 70% of MM patients and 50% of MGUS patients (8,9,15,18,20) and have been proposed as the primary event in the process leading to MM (10,11,22,36). Using image cytometry and cIg-FISH, 73% of MGUS patients showed chromosome changes, a percentage higher than that related to IgH translocations.…”

“…With some exceptions (14,15), conventional cytogenetic study is unsuccessful in MGUS, and most information about cytogenetic status has been drawn from interphase FISH studies done on bone marrow plasma cells (BMPC). Numerical chromosome changes are observed in up to 60% (16 -19) and IgH translocations in up to 48% of patients tested (9,18,20,21).…”

“…Thus far, little is known about the real incidence of hyperdiploidy and hypodiploidy in MGUS due to inability to do conventional cytogenetic study in most instances (14,15). Flow cytometry (FCM), a good method to ascertain hyperdiploidy in MM patients (24 -27), was applied to MGUS patients and, although the number of cases reported was low, showed that some patients showed a hyperdiploid PC clone (24 -26, 28, 29).…”