Approximately 55% to 60% of patients with newly diagnosed MM are characterized by a hyperdiploid karyotype with the number of chromosomes ranging from 48 to 74 and trisomies of odd-numbered chromosomes including 3, 5, 7, 9, 11, 15, 19, and 21 and few IGH translocations (Figs. 1 and 2). Among these gains, chromosomes 9, 15, 19, and 21 are usually acquired first, and may be followed by trisomy of chromosomes 3, 5, and 7. These chromosomal abnormalities are considered primary genomic changes in the early pre-malignant stage and theoretically involved in disease pathogenesis. Therefore, the prognostic relevance of numerical abnormalities using classic cytogenetics is unknown, although the presence of abnormal metaphases cells is an indicator of poor prognosis. However, hyperdiploid MM detected by FISH tend to have a better prognosis than do those with nonhyperdiploid disease. This effect is lost in cases where hyperdiploidy is associated with other genetic markers of progression such as gain of 1q21 and deletion of 17p13. Many studies have shown a median OS of 60.8 months for hyper diploid patients with MM with no adverse cytogenetic lesions as compared to 33.7 months for those hyperdiploid patients with MM who had one or more of the adverse cytogenetic abnormalities such as t(4;14), t(14;16), t(14;20), del(17p), and +1q (see Figs. 3 and 4). The exact origins of hyperdiploidy remain unknown, although four processes are proposed: (1) a near-haploid cell doubles all chromosomes; (2) a tetraploid cell experiences subsequent loss of chromosomes; (3) a diploid cell undergoes sequential gains of chromosomes during clonal evolution; and (4) a diploid cell suffers a single mitotic catastrophe resulting in simultaneous gain of additional chromosomes. The data suggest that a single mitotic catastrophe, such as failed mitotic event, may be the most likely mechanism of acquisition of hyperdiploidy, which may be followed by the secondary gain of extra chromosomes during subclonal evolution. In some patients hyperdiploidy may precede primary translocations affecting IGH as revealed by studies using single cell sequencing analysis. In general, hyperdiploidy is associated with more favorable survival than hypodiploidy; however, adverse cytogenetic features, such as +1q, del(17p), and t(4;14) predict worse survival than hyper diploidy alone.
Fig1. A complex hyperdiploid karyotype from a patient with multiple myeloma (A) and after multicolor FISH (B), which was used to resolve a number of complex derivative chromosomes: 54, X,−X, der(1)t(1;8)(q34;q21q24)x2, der(2) del(2)(p13p25)t(X;2)(p21p22.3;p13), t(3;8)(q27;q22q24), +i(5)(p13p15), +7, der(8;17)(p23;q11.2q25), +der(11)t(1;9;11(?p36;q21q31;p15), t(11;20)(q13;q11.2, der(11)t(9;11)(q13q34;q25), t(12;13)9(p13;q14q34), +15, +19, +20.
Fig2. CYTOGENOMIC PROFILES IN MULTIPLE MYELOMA. Summary of genomic profiles and recurrence of chromosomal alterations in pri mary tumors demonstrated by array comparative genomic hybridization. The recurrence plot mirrors the frequencies of previously reported chromosomal gains and losses, including the deletions of 1p and amplifications of 1q. Integer-value recurrence of copy number aberrations across the samples in segmented data is plotted on the y-axis. The x-axis is in chromosomal order. Dark red or green bands denote the number of samples with gain or loss of chromosome material, and bright red or green bars represent the number of samples showing amplification or deletion. Black dots show focal deletions of the kappa (2p12), IgH (14q32), and lambda (22q11) loci physiologic in B-cell postgerminal center neoplasms. (Reprinted with permission from Carasco DR, Tonon G, Huang Y, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;4:313.)
Fig3. REPRESENTATIVE PARTIAL KARYOTYPES OF METAPHASE CHROMOSOMES DEMONSTRATING THE DIFFERENT TYPES AND DEGREE OF AMPLIFICATION OF CHROMOSOME 1. FISH probes for 1q12 (red), 1q21 (green), and 16q11 (aqua) are shown on inverted DAPI images of chromosomes. (A) Interstitial deletion of 1p (arrow) in the homolog on the left and a direct dup1q12–q23 on chromosome on the right. (B) Normal homolog 1 on the left and the abnormal homolog on the right, demonstrating both an interstitial deletion of 1p and the amplification of 1q in the same chromosome. Note four copies of 1q21 (arrows) in an inverted duplication pattern. (C) Examples of an unbalanced whole-arm translocation of 1q to chromosome 16q. Chromosomes 1 are on the left, and chromosomes 16 are on the right. Aqua probe denotes 16q11 heterochromatin. Note the loss of 16q distal to the aqua probe on the der(1;16)(q10;p10). The entire long arm 1q is translocated to the pericentromeric region of 16q, and a total of three copies of 1q21 (arrows) are present. (D) Examples of an unbalanced whole-arm translocation of 1q to 19q. Note that the result of this translocation is the der(1;19)(q10;p10) chromosome, which shows an extra copy of 1q21 (arrows) and loss of the entire 19q. (E) Examples of jumping 1q, in which all or a part of 1q is translocated to three copies of 1q (arrows) on the three different nonhomologous chromosomes. The whole-arm der(19)(q10;p10) in this case is the same type seen in patient in (D). The der(21) results from the segmental translocation of the inverted dup of 1q to the short arm of 21. The der(22) results from the whole-arm 1q translocated to the short arm of 22. (F) Homologous of chromosome 1 demonstrating amplification of 1q12–q23 by breakage-fusion-bridge cycles. Note multiple copies of 1q21 (arrows) on the abnormal homologue on the right. The copies of the 1q12–q23 amplicon occur in an inverted repeated pattern, with a deletion of the 1q distal to the amplified region. Dotted lines between normal homologue 1 (left) and abnormal homologue denote the size of expansion of the 1q12–q23 region by break-fusion-bridge cycles. FISH, fluorescence in situ hybridization. (Reprinted from Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet. 2011;204:3, with permission.)
Fig4. Bone marrow nuclei from a patient with multiple myeloma after hybridization using three probes: 1q21 (aqua), PBX1 (red) localized on 1q25, and TCF3 (green) localized on 19q13. Note amplification (up to 17 copies) of 1q21 an2 1q25 (white arrows), as well as multiple copies of 19q loci. Amplification of 1q21–q25 is associated with disease progression and very poor prognosis in multiple myeloma despite novel therapies.
