An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome

Abstract

Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term "Jumping 1q Syndrome."

Fig. 1. Partial karyotypes from patient no 22 demonstrating subclonal heterogeneity and the ongoing regeneration 1q21 CNAs.

FISH probes 1q12(red) and 1q21 (green) and SKY classified colors for chromosomes 1 (yellow), 2 (crimson), 5 (orange), and 19 (green) (a–h). Blue arrows depict evolving lineage of the 1q12 aberrations appearing in the different subclones. Subclone A demonstrates transient triradial chromosome 1q12 (a), which regenerates extra copies of 1q21 (arrows). Note branching of 1q12 pericentromeric heterochromatin (arrow) leading to the duplicate 1q arm displaying the extra copy of the 1q21. b A JT1q12 to RC19 results in a der(19) with gain of 1q and a concomitant whole-arm deletion of 19q. c A reduplication of the der(19) shows an additional direct duplication of the 1q12-q21. A total of six copies of 1q21 were identified in this subclone (normal chromosome 1 not shown). In subclone B (d, e), the evolution of der(19)s is demonstrated by a complex multichromosome rearrangement in one of the der(19)s (d). SKY identified segments of chromosomes 5 and 2 translocated distal to 1q21 (d). The other der(19) in this subclone demonstrates the transient decondensation and breakage in the 1q12 pericentromeric heterochromatin (e). This subclone shows five copies of 1q21 (normal chromosomes 1 not shown). The further progression of 1q12 aberrations in subclone B is evidenced by the new aberrations found in subclone C, which shows the decondensation and breakage in 1q12 (f), and the generation of a novel iso (1q) with four copies each of 1q12 and 1q21 (h). This subclone shows a total of nine copies of 1q21 (normal chromosomes 1 not shown)

Fig. 2. Metaphase cells from patients demonstrating different types of progression events involving isochromosomes 1q.

Top patient no 7 (a–d) showing progressive gains of both 1q12 and 1q21 resulting from BFB cycle amplifications of the 1q12–1q21 region. The 1q12 breakpoints generate gains of 1q21 in extended ladder-like pattern. FISH probes 1q12(red) and 1q21 (green). Normal chromosomes 1 from these cells (a–d) not shown. a An isochromosome 1q showing an alternating pattern of 1q12 and 1q21 with four copies of each (arrows). b Increased copy number amplification of both 1q21 and 1q12 resulting in six copies of both 1q12 and 1q21 in this chromosome. c The iso(1q) in this cell shows the characteristic alternating copies of 1q12 and 1q21 and extended ladder-like structure seen in BFB cycles demonstrating eight copies of both 1q12 and 1q21. d A cell with a total of ten copies of both 1q12 and 1q21 with six copies on the iso(1q) and four small extra-chromosomal acentric rings each with single copies of 1q12 and 1q21. Bottom Partial karyotypes from patient no 4 demonstrating two isochromosome 1qs with intra-arm heterogeneity of both CNAs and loci position of 1q12 and 1q21. FISH probes 1q12 (red) and 1q21 (green). a This cell shows the expected copy number and loci position for two “normal” isochromosomes 1q with four copies of 1q12 and 1q21. b The iso(1q) on left shows normal copy number and positions for 1q12 and 1q21, while the iso(1q) on the right shows the 1q21 locus has inverted distally in both arms. c The iso(1q) on left shows the normal copy number and positions for 1q12 and 1q21; however, the iso(1q) on right shows four copies of 1q12 and three copies 1q21 (arrows) with unequal CNAs between the arms. d Both iso(1q)s show intra-arm changes, the iso(1q) on left shows two copies of 1q12 and three copies of 1q21, while the iso(1q) on the right shows a large focal amplification of 1q12. The copy number of 1q21 in this cell is five. e A cell showing eight copies of 1q12 (arrows) and seven copies of 1q21 distributed among three chromosomes. Left, iso(1q) with three copies 1q12 and two copies of 1q21. Center, iso(1q) with four copies of both 1q12 and 1q21 displaced distally of normal positions. Right single copies of 1q12 and 1q21 on a der(16)

Fig. 3. Partial karyotypes of three patients showing concomitant 17p deletions originating from a jumping translocation of 1q12 to 17p.

FISH probes for 1q12 (red) and 1q21 (green) are shown on the left. SKY image-classified colors for chromosome 1 (yellow), chromosome 3 (gray), chromosome 9 (white), chromosome 17 (blue), and chromosome 18 (fuchsia), and chromosome 22 (pink). FISH probes for TP53 (green) and ERBB2 (red). a Patient no 30 showing chromosomes in brackets from left to right, normal chromosomes 1 with FISH (left) and SKY (right). Middle brackets show two different der(3) RCs both with 1q12 and 1q21. In the brackets on right the chromosomes 17 show hybridization of the normal chromosome 17 with probes TP53 (green) and ERBB2 (red) in their normal positions. The der(1;17) shows the deletion of TP53 (no green signal) and ERBB2 (red) in normal position. In the right bracket the der(1;17) is shown with the 1q replacing 17p and normal positions of 1q12 (red) and 1q21 (green) on 1q. The SKY on the right shows 1q (yellow) replacing 17p and the 17q (blue). b Patient no 42 with brackets on far left showing 1q FISH with one normal chromosome 1 (left) and a small der(1) on (right) with large deletions of both 1p and 1q. Bracket middle left shows a der(9) with 1q12 and 1q21 (arrows) on the distal 9q. Brackets middle right shows the normal 17 showing TP53 (green) and ERBB2 (red), the der(1;17) showing loss of TP53 (green) and presence of ERBB2 (red). The bracket on right shows the same der(1;17) chromosome hybridized with 1q12 (red) and 1q21(green) and SKY (right) showing 1q (yellow) replacing the short arm of 17 (blue). Far right bracket shows 1q FISH (left) with 1q12 and 1q21 on 22, and SKY of der(22) with 1q (yellow) translocated to 22 (pink). A total of five copies of 1q21, three of which are distributed to RCs 9q, 17p, and 22q. c Patient no 49 in brackets on the left are normal chromosomes 1 by FISH and SKY. Middle brackets show normal TP53 (green) and ERBB2 (red) left and der(17) with deleted 17p (green) by FISH. The brackets on right show normal 1q12 and 1q21 by FISH and 1q replacing 17p (blue) by 1q (yellow) by SKY. Bracket on far right shows an inverted duplication of 1q21 on chromosome 18 with copies of 1q21 on both sides of 1q12 (left) by FISH. SKY showing 1q (yellow) on distal end of 18 (fuchsia)

Fig. 4. Partial karyotypes of patient no 2 demonstrating the different types of transient 1q12 aberrations that continually regenerate gains of 1q21 and MYC.

a Chromosome 8 showing metaphase FISH of JT1q12 to the der(8) hybridized on left with 1q12 (red) and 1q21 (green) and on right the same chromosome hybridized with MYC (red) and 16p (green). b The der(8) (left) hybridized first with chromosome 1 probes demonstrates a direct duplication of 1q12 (red) and 1q21 (green). Importantly, the hybridization with FISH probes for MYC and 16p (on right) shows a cryptic duplication and concomitant amp of the region spanning 1q12-1q21, MYC, and 16p (arrows). c Breakage at 1q12 and the loss of 1q distal to 1q12 resulted in a sister chromatid fusion (SCF) at 1q12 on the distal 8q. d The SCF aberration resulted in the subsequent formation of a dicentric 8 showing 1q12 (arrow) as the bridging point connecting the dicentric 8. e The outcome of BFB cycles of the dicentric (8) is the amplification of MYC and 16p in an inverted duplication pattern typical of BFB amplification. This chromosome has three copies of MYC and two of 16p. f A dispersed insertion of MYC and 16p into one of the previously normal chromosomes 1. g The regeneration of additional copies of 1q21 is demonstrated by a triradial of 1q12 (red) on distal der(8q) showing an extra copy of 1q21 (green) transiently attached to each chromatid of the der(8q). Note also in this cell the presence of an extra acentric lagging copy of 1q with signals for both 1q12 (red) and 1q21 (green)

Fig. 5. A partial karyotype of patient no 14 showing multiple JT1q12s resulting in dispersed insertions of the MET region (7q31).

This clone shows a total of six copies of 1q12 and 1q21, and four copies of MET are present in this cell, normal chromosomes 1, 6, and 7 not shown. a Metaphase FISH shows two copies each for 1q12 (red) and 1q21(green) on the der(7q) (left), rehybridization with FISH probes for 7q21 (red) and MET (7q31, green) (middle) indicates the normal locations for these loci, and SKY classification colors (right) shows 1q (yellow) on distal 7q (salmon). b FISH probes for 1q12 (red) and 1q21 (green) shows one copy of both probes translocated on 6q (left), when rehybridized with MET (7q31, green), the 6q shows MET is inserted resulting in a der(6) with extra copies of 1q12, 1q21, and MET (middle). The SKY on right shows 6 (magenta), 7q MET regions (salmon) in middle, and 1q (yellow) distal. c Fish probes for 1q12 and 1q21 (left) shows an apparent direct duplication on 1q; the same chromosome 1 rehybridized with MET (middle) shows an insertion of MET into the 1q12 pericentromeric region of chromosome 1. On right SKY colors show insertion of 7q (salmon) material into chromosome 1q (yellow)

Fig. 6. Characterization of possible types of JT1q12 chromosome instability.

Depiction of normal chromosome 1 (yellow), centromere (black), 1q12 (red), and 1q21 (green) (a). Two transient aberrations of 1q12 are precursors to subsequent clonal aberrations, the first being 1q12 decondensation and breakage (b), which leads to the formation of 1q12 triradials (c). The extra copy of 1q generated by the triradial of 1q12 can result in multiple types of unbalanced CNAs. A JT1q12 to 17p can result in the concomitant gain of both 1q12 and 1q21 and deletion of 17p (TP53) (d). Extra copies of 1q12 that do not successfully jump to an RC result in acentric lagging copies of 1q and subsequent micronuclei (e). A JT1q12 to 8q (f) demonstrates ongoing instability including the two sublcones. Subclone 1 involved the loss of 1q from 8q, resulting in a sister chromatid fusion (SCF) (arrow) at 1q12 (g). Subsequent formation of dicentric 8 and a 1q12 bridge (h) is an intermediate step in BFB cycles resulting in the amp of MYC and 16pter (i). In subclone 2, 1q12 instability is demonstrated by a triradial of 1q on 8q resulting in the generation of additional copies of 1q21 (j). The additional copies of MYC, 16p, 1q12, and 1q21 are subsequently translocated to a normal chromosome 1q resulting in an insertion (k). A JT1q12 to 7q (l) subsequently results in insertion of MET into multiple nonhomologous chromosomes, including both 6q, causing a near arm-length deletion in 6q (m), and also to an RC 1q resulting in insertion of MET into a normal chromosome 1 (n)