Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma

Abstract

Summary. Multicolour spectral karyotyping (SKY) was performed on primary tumour specimens from 100 patients with multiple myeloma (MM) that showed complex clonal chromosome aberrations not fully characterized by G-banding. In this study, SKY was able to identify or revise translocations with breakpoints involving 14q32, 11q13 or 8q24 in 32 patients (32%). Five new recurring translocations were identified, two of which involved chromosome 22. A subtle reciprocal translocation t(14;22) (q32;q11,12) was identified using SKY in two patients and a second, much larger, translocation t(11;22)(q13;q13) was identified using G-banding in three patients. A third new translocation was identified in two patients using SKY and G-banding as der(7)t(7;7)(p15,22;q22,32). Twentythree patients (23%) showed the loss of 8p by whole-arm translocations with different whole-arm donor chromosomes. Among this group, two new recurring whole-arm translocations involving the centromeric breakpoint 8q10 were identified as der(8;20)(q10;q10) and der(8;18) (q10;q10) in three patients each. In addition, a novel pattern of three-way translocations involving the clonal evolution of the t(8;22)(q24;q11) by the subsequent loss of 8p by whole-arm translocations was found in three patients. The chromosome instability identified here demonstrates that the loss of 8p can occur by multiple whole-arm translocations, indicating a new pathway for the loss of a specific chromosome region in MM.

Chromosome translocations in multiple myeloma

“…A few other loci have been reported as infrequent recurrent 14q32 translocation partners in MM (AvetLoiseau et al, 1999a(AvetLoiseau et al, , 2001Bergsagel et al, 1996;Nishida et al, 1997;Rao et al, 1998;Sawyer et al, 1998Sawyer et al, , 2000. Mostly these breakpoints have not been cloned, nor the dysregulated genes characterized.…”

“…Third, the IgH locus (14q32) has a telomeric location, and many of the partner loci have telomeric (4p16; 6p25) or subtelomeric (16q23) locations. Two-or three-color FISH analyses or spectral karyotypic (SKY) analyses of metaphase chromosomes largely solve the second and third problems, with the major exception being that telomeric breakpoints (4p16; 6p25) are not detected by SKY analyses (Sawyer et al, 2000). Interphase FISH analyses using probes that¯ank an Ig locus to detect split signals or a probe from one end of an Ig locus together with a probe from a speci®c chromosomal region to detect fusion signals permit a comprehensive assessment of Ig translocations in all tumor cells, including MGUS.…”

“…Translocation t(14;16) (q32;q23) is identi®ed in 5/39 (13%) MM cell lines, and in 5 ± 10% of patients with MM (Chesi et al, 1998a;Sawyer et al, 1998Sawyer et al, , 2000. The ®ve cloned breakpoints on 16q23 occur over a region 550 ± 1350 kb centromeric to c-maf, all but one of them within the 800 kb intron of an oxidoreductase gene, WWOX/FOR (Bednarek et al, 2000;.…”

“…The location of the t(1;14) (q21;q32) breakpoint far downstream of the Sa region suggests that this likely represents a secondary translocation, at least in this tumor cell line. From SKY analyses of 150 tumors, the incidence of the t(1;14) (q21;q32) translocation is about 1 ± 2% of advanced intramedullary MM tumors (Sawyer et al, 1998(Sawyer et al, , 2000.…”

Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach

“…The transcription factor c-maf is transcriptionally up-regulated as a result of this translocation (27,29). The t(14;16) is difficult to detect by conventional karyotypes but has been reported in 7% of MM patients with abnormal metaphases studied by SKY (30). In two series of patients, the t(14;16)(q32;q23) was associated with a shorter survival among patients treated with conventional chemotherapy and HDT (27,31).…”