Cancer Cytogenetics


The development and progression of cancer is often associated with the acquisition of nonrandom chromosome aberrations. These can produce changes in gene loci, resulting in either the deregulated expression of an oncogene, the production of a chimaeric fusion gene or inactivation of a tumour suppressor gene (TSG). Chromosome aberrations are particularly important in the diagnosis, prognosis, progression, monitoring and treatment of acute and chronic leukaemia, small round cell tumours and central nervous system tumours. Numerical chromosome changes typically result in gain or loss of a few chromosomes, but can also produce changes in ploidy. Translocations, mostly affecting oncogenes, account for the majority of disease‐specific structural chromosome aberrations, whereas deletions are more important in TSGs. Knowledge of the nature and mechanisms of action of the genes involved is important in understanding how they contribute to the genesis, promotion and progression of this complex disease.

Key concepts

  • Chimaeric gene fusion – the most frequent, recurrent oncogenic change usually produced via chromosome translocation. Two previously separate and independent genes are fused to form a single unique contiguous gene, and the resultant gene product has oncogenic properties.

  • Oncogene deregulation – juxtapositioning of an oncogene with the enhancer region of a T‐cell receptor gene or an Immunoglobulin gene results in overexpression of the oncogene protein product. This is most commonly a result of a chromosome translocation.

  • Oncogene amplification – a selective, unscheduled increase in gene copy number enabling a cell to meet the increased transcriptional demands of neoplastic transformation. This is seen as double minutes or as a chromosome duplication.

  • Tumour suppressor gene inactivation – removal of the growth control functions of a TSG either by mutation or loss, after which the cell may fail to keep a cancer from developing, transforming the cell to a cancer phenotype.

  • Loss of heterozygosity – the key mechanism of inactivation of a TSG. At a locus heterozygous for a deleterious mutant allele and a normal allele, a deletion or other mutation in the normal allele renders the cell hemizygous or homozygous for the deleterious allele.

Keywords: oncogene; tumour suppressor gene; translocation; deletion; duplication

Figure 1.

Illustration shows BCRABL fusion gene following t(9;22) Philadelphia translocation. In chronic myeloid leukaemia (CML) breakage is within the M‐BCR region and this is shown to produce an 8.5‐kb fusion transcript, which generates a 210‐kDa fusion protein. In acute lymphoblastic leukaemia (ALL), the 22q break is typically within the m‐BCR region. This produces a 7.5‐kb fusion transcript, which generates a smaller 190‐kDa fusion protein. Note that, in both cases, the critical fusion transcript is on the der(22).

Figure 2.

Illustration showing juxtapositioning of MYC from 8q to constant (C) region of the IGH locus at 14q32. Note that the entire coding region (exons 2 and 3) of MYC is translocated in a head‐to‐head (5′ to 5′) manner. The consequence is upregulation of a structurally normal cmyc protein.

Figure 3.

Karyotype of Ewing sarcoma tumour with the pathognomonic t(11;22)(q24;q12). This case also contains 1q gain in the form of an additional isochromosome of 1q. The karyotype here is defined as ‘simple’, i.e. with fewer than five independent chromosome changes. The interphase FISH image shows EWSR1 gene rearrangement. A break‐apart Vysis EWSR1 FISH probe demonstrates splitting of the 5′EWSR1 (green) signal from the 3′EWSR1 (red) signal. The normal (fusion) EWSR1 locus is seen as a yellow signal.

Figure 4.

FISH images using a Zytovision PAX7FKHR probe kit in a case of alveolar rhabdomyosarcoma with PAX7FKHR amplification. The interphase cell (left) shows multiple yellow fusion signals of the PAX7 (green) and FKHR (red) probes. The metaphase cell (right) shows PAX7FKHR fusion signals present on supernumerary double minute structures (yellow). Only one discrete PAX7 signal on the normal chromosome 1 and only one discrete FKHR signal on the normal chromosome 13 is seen. One chromosome 1 homologue and one chromosome 13 homologue is deleted for PAX7 and FKHR, respectively. It is assumed that a t(1;13) translocation has originally occurred and the resultant PAX7FKHR fusion product has broken off from the derivative chromosome 13 to produce the episomic double minutes.



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Roberts, Paul(Dec 2008) Cancer Cytogenetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001476.pub2]