Timing of acquisition of deletion 13 in plasma cell dyscrasias is dependent on genetic context.
BACKGROUND
Multiple myeloma, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma harbor common chromosomal abnormalities but the prevalence and relative association of aberrations in these diagnostic groups remains controversial. We investigated these aspects in a large series of patients.


METHODS
Chromosome 13 deletion (Delta13), deletion of TP53, ploidy status and immunoglobulin heavy chain (IgH) translocations were evaluated by fluorescence in situ hybridization in patients with monoclonal gammopathy of undetermined significance (n=189), smoldering multiple myeloma (n=127) and multiple myeloma (n=400).


RESULTS
Overall, Delta13 (25%, 34% and 47%), 16q23 deletions (6%, 8% and 21%) and 17p13 deletions (3%, 1% and 10%) were less frequent in patients with monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in those with multiple myeloma. When distinct genetic groups were considered, no differences in the prevalence of Delta13 were found with t(4;14)(p16;q32) and t(14;16)(q32;q23) among the three diagnostic groups; in contrast Delta13 was rarer in t(11;14)(q13;q32) in patients with monoclonal gammopathy (1/28) and smoldering myeloma (2/13) than in those with multiple myeloma (40%). Similar results were seen for the few t(6;14)(p21;q32) cases: 0/3 patients with monoclonal gammopathy or smoldering myeloma had the Delta13, whereas 4/6 (67%) patients with multiple myeloma and this translocation also had the deletion. In multiple myeloma patients with both an IgH translocation and Delta13, the proportions of cells affected by the two abnormalities were similar, as was the case for t(4;14) and t(14;16) monoclonal gammopathy patients positive for Delta13. In contrast, in monoclonal gammopathy patients with t(14;20)(q32;q11), the translocation was present in almost all cells, while the Delta13 was present in only a sub-population.


CONCLUSIONS
These results indicate that the presence and time of occurrence of Delta13 depends on the presence of specific concurrent abnormalities. The observation that Delta13 was extremely rare in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma with translocations directly involving cyclin D genes (CCND1 and CCND3) suggest a possible role of Delta13 in the progression of the disease specifically in these genetic sub-groups. (clinicaltrials.gov identifier: ISRCTN 68454111; UKCRN ID 1176).
Chiecchio
Laura
L
Leukaemia Research Fund UK Myeloma Forum Cytogenetics Group, Human Genetics Division, University of Southampton, Wessex Regional Genetics Laboratory, Salisbury District Hospital, Wilts, UK. laura.chiecchio@salisbury.nhs.uk
Dagrada
Gian Paolo
GP
Ibrahim
Ashraf H
AH
Dachs Cabanas
Elizabet
E
Protheroe
Rebecca K M
RK
Stockley
David M
DM
Orchard
Kim H
KH
Cross
Nicholas C P
NC
Harrison
Christine J
CJ
Ross
Fiona M
FM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D056741:Cyclin D / Q000235:genetics; D015321:Gene Rearrangement; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000473:pathology; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D010265:Paraproteinemias / Q000235:genetics* / Q000473:pathology; D013997:Time Factors; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D056741:Cyclin D; D007143:Immunoglobulin Heavy Chains; D016159:Tumor Suppressor Protein p53