Cancer: Chromosomal Abnormalities

Abstract

Most cancer cells have acquired clonal chromosome abnormalities. An increasing number of characteristic aberrations, in particular balanced changes, are with remarkable specificity associated with distinctive morphological and clinical disease characteristics. The identification of these recurrent aberrations has several important implications. First, cytogenetics has become an increasingly important tool in the clinical management of cancer patients to help establish a correct diagnosis, to predict prognosis and to select the most appropriate treatment. Second, the cytogenetic information has provided invaluable help to identify genes of importance in the carcinogenic process by focusing the attention to chromosomal sites that may harbour genes which when rearranged lead to neoplasia. Practically, all balanced structural rearrangements that have been characterised at the molecular level have been found to exert their action through one of the two alternative mechanisms: deregulation, usually overexpression, of a seemingly normal gene in one of the breakpoints, or the creation of an abnormal hybrid gene through fusion of parts of two genes, one in each breakpoint.

Key Concepts

  • Chromosome aberrations are a characteristic feature of neoplasia.
  • Chromosome abnormalities have been reported in almost 70 000 human neoplasms.
  • Recurrent balanced chromosome rearrangements, in particular translocations, are associated with distinctive tumour characteristics.
  • Cancer‐associated chromosome changes are of clinical importance for diagnosis, prognosis and treatment.
  • The breakpoints of balanced structural chromosome aberrations point at the locations of cancer‐relevant genes.
  • Cancer‐associated structural chromosome abnormalities lead to the formation of hybrid genes through fusions of parts of two genes located in the breakpoints.
  • Almost 800 gene fusions created by an acquired chromosome change are known.

Keywords: cancer; leukaemia; neoplasia; chromosome aberrations; oncogenes; fusion genes; cytogenetics; molecular cytogenetics; translocations; cancer diagnosis

Figure 1. The translocation t(8;14)(q24;q32) in Burkitt lymphoma leads to deregulation of the MYC gene located in chromosome band 8q24 through its juxtaposition with regulatory elements of the immunoglobulin heavy chain (IGH) gene in chromosome band 14q32. The MYC gene has three exons, and is oriented with its 5′ end towards the centromere of chromosome 8; the breakpoints in 8q24 show considerable variability, but the breaks always take place upstream of exon 2, the first coding exon of MYC. The breaks in IGH usually take place in switch regions but can also involve joining (JH) or occasionally other gene regions. As a consequence of the translocation, the MYC gene (i.e. its two protein‐encoding exons) becomes constitutively activated because its expression is driven by immunoglobulin enhancers (E). The IGH gene is oriented with its 5′ part towards the telomere, so the translocation leads to a 5′–5′ (head‐to‐head) fusion of the two genes.
Figure 2. The translocation t(9;22)(q34;q11) in chronic myeloid leukaemia juxtaposes the 5′ part of the BCR gene in chromosome band 22q11 with the 3′ part of the ABL1 gene in 9q34, resulting in the creation of a hybrid BCR/ABL1 gene. The ABL1 gene is oriented with its 5′ end towards the centromere of chromosome 9. The gene contains two alternative first exons, 1b and 1a, followed by exons 2–11. The breakpoints are scattered over a large area at the 5′ part of the gene, always upstream of exon 2. The BCR gene has its 5′ end towards the centromere of chromosome 22; the gene has 23 exons. In most patients with chronic myeloid leukaemia, the break occurs in a ‘major breakpoint cluster region’ spanning exons 12–16. As a consequence of the translocation, an in‐frame BCR/ABL1 fusion transcript is produced.
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Mitelman, Felix(Aug 2017) Cancer: Chromosomal Abnormalities. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005552.pub3]