Abnormalities at the chromosomal level
The majority of chromosomal abnormalities in myeloma affect the control of the cell cycle and/or programmed cell death (apoptosis). When these are disrupted, malignancy occurs.
Research using sensitive cytogenetic tests, such as fluorescence in situ hybridisation (FISH), have demonstrated that it is possible to identify chromosomal abnormalities from bone marrow biopsy samples in at least 90% of cases of myeloma.
FISH analysis involves staining the chromosomes with fluorescent markers and visualising them under a microscope. When stained, chromosomes look like strings with light and dark ‘bands’. Each chromosome arm is defined further by numbering the bands; the higher the number, the further the area is from the centromere or the pinched area of the chromosome.
All chromosomes have two arms: a short arm, “p” (petit) and a long arm, “q”. Some chromosomes such as 13, 14 and 15 have very small p arms. The arms are connected by a central point called the centromere.
Figure 6: Structure of a chromosome
In myeloma, chromosomal abnormalities generally involve exchanges (or translocations), deletions or duplications of parts of or whole chromosomes. The absence of one chromosome in a pair of chromosomes is called a ‘monosomy’ and the presence of an extra chromosome is called ‘trisomy’.
Translocations of genetic material between chromosomes are common. This is caused by a breakage in at least two chromosomes followed by exchange of genetic material between them. Translocations are indicated by the letter t, followed by the numbers of the involved chromosomes in brackets. Sometimes the location may be included and referred to as number e.g. 14q32. This is the distance from the centromere.
Many chromosomal abnormalities can occur in myeloma, although the most frequent are shown in Table 2. These aberrations are found only in malignant plasma cells, meaning they are not inherited genetic abnormalities but are acquired. They determine the nature and biology of the myeloma and so correlate with prognosis. Genetic abnormalities continue to be acquired over the course of the disease and typically, relapsed patients have more of them than a newly diagnosed patient.
Table 2: Most common cytogenetic abnormalities in myeloma
| Chromosome | Type of chromosome abberation |
|---|---|
| 1 | Gain 1q (gain of part of the long arm of chromosome 1 Del 1p (partial deletion of the short arm of chromosome 1) |
| 14 | Translocations of
|
| 13 | Monosomy 13 (complete loss of chromosome 13) Del 13q (partial deletions of the long arm of chromosome 13) |
| 17 | Del 17p (partial deletion of the short arm of chromosome 17) |
| Note: q= long arm, p= short arm, del = deletion | |
14q translocations
Chromosome 14q is the site of the normal gene for the heavy chain of the Ig molecule. Rearrangement of the genetic material is normally required for a B cell to be able to make Igs. It is not surprising, therefore, that this is a common site of translocations in myeloma.
Translocations at 14q32 are found in around 50% of patients. For example, one relatively common example is translocation t(4;14) (p16;q32). In this case, chromosome 14 broke at the point designated 32 of the long arm and chromosome 4 broke at the point designated 16 on the short arm. The respective parts then rejoined to the “wrong” chromosome disrupting the genes coded in these regions. A number of these genes regulate the cell cycle and so these changes lead to uncontrolled cell growth. Examples include: 11q13, 4p16 and 16q23.
Cytogenetics in myeloma remains an important area of ongoing research. To learn more about the impact of chromosomal abnormalities as prognostic factors, and their significance in the management of myeloma, see Module 4 – Staging and prognosis of myeloma
Watch the following animation which describes chromosome abnormalities in myeloma.
Further reading
Clarke et al. (2024) Chromosomal defects in multiple myeloma. Blood Reviews (64) 101168
Pertesi et al (2020) Genetic predisposition for multiple myeloma. Leukemia (34) 697–708