Mechanisms of Chromosome Translocations in Cancer


Chromosome translocations have long been known to be causative events in cancer. First observed as recurrent translocations in lymphomas and leukaemias, translocations are also found in solid tumours. One of the key hallmarks of cancer is genome instability, and chromosome translocations represent a critical form of genome instability that reflects mis‐repair of DNA double‐strand breaks (DSBs). DSBs are repaired by two main pathways, non‐homologous end joining and homologous recombination, and chromosome translocations can be created by both of these pathways. Many translocations associated with specific cancers are recurrent, reflecting selective pressure for inactivated tumour suppressor genes or activated oncogenes, which are early drivers of cancer phenotypes. Cancer therapeutics, including DNA reactive chemicals, topoisomerase inhibitors and radiation, are effective cancer treatments, but they can induce translocation‐mediated secondary malignancies at significant frequencies. Reducing the risk of these sequelae is an important goal in cancer research.

Key Concepts

  • Chromosome translocations are critical genomic rearrangements that are frequently found in lymphoid and solid tumours and other diseases.
  • Translocations arise when DNA double‐strand breaks arise simultaneously on two separate chromosomes and are mis‐rejoined.
  • Translocations observed in cancer may inactivate tumour suppressor genes or activate oncogenes by gene fusion or juxtaposition of a strong promoter with a proto‐oncogene.
  • Translocations are formed primarily through alternative non‐homologous end joining, but other double‐strand break repair mechanisms can contribute to translocation spectra, including classical non‐homologous end joining, homologous recombination and single‐strand annealing.
  • Cancer therapeutics may cause translocations that generate secondary, therapy‐induced cancers.
  • Translocation efficiency and junction positions are regulated by many factors including programmed DNA double‐strand breaks, spontaneous and induced DNA damage, DNA repair pathways, structural elements in DNA sequences such as repeated sequences and palindromes, relative locations chromosomes within nuclei and epigenetic factors.

Keywords: genome instability; DNA repair; chromatin; cancer therapy; oncogenes; tumour suppressor genes; epigenetics; non‐homologous end joining; homologous recombination

Figure 1. Types and consequences of chromosome translocations. (a) Balanced translocations result from reciprocal exchange in which little or no sequence information is lost. Depending on the position of the exchange (X), chromosome translocations can produce stable mono‐centric chromosomes (left) or unstable dicentric and acentric chromosomes (right). (b) Unbalanced translocations result from nonreciprocal exchange in which a segment from one chromosome is lost. (c) Translocations can activate proto‐oncogenes by juxtaposing a strong promoter and a proto‐oncogene, causing overexpression. (d) Translocation breakpoints within genes can cause gene inactivation, that is, of a tumour suppressor. (e) Translocations can fuse two genes (or specific exons, e.g. Ex1, Ex2) to create novel oncogenes. In this illustration the exchange occurs within introns.
Figure 2. DSB repair by NHEJ and HR. (a) NHEJ comprises two subpathways, cNHEJ and aNHEJ. Both initiate with DSB recognition and limited end‐processing by the MRN complex. 53BP1, RIF1 and Ku suppress end resection. Ku binds DNA ends and recruits DNA‐PKcs, which aligns ends for repair by Ligase IV and its accessory factors XRCC4 and XLF. aNHEJ requires limited resection by MRN and CtIP to expose microhomologies, which align ends, forming flaps that are trimmed, and repair is completed by Ligase III and XRCC1. (b) HR initiates with limited resection by MRN and CtIP, and more extensive resection is catalysed by Exo1 or Dna2. RPA binds single‐stranded DNA and is exchanged for RAD51 by many mediator proteins (not shown). The RAD51 nucleoprotein filament invades a homologous sequence and the 3′ end is extended by DNA polymerase δ. The extended strand can be released to anneal with the resected strand on the opposite side of the DSB (SDSA; no crossover), or the second end can invade, forming a double Holliday junction that can be resolved with or without a crossover; the crossover pathway can produce a translocation if HR occurs between homologous sequences on different chromosomes.
Figure 3. DSB repair by single‐strand annealing. (a) SSA involves extensive resection as with HR (Figureb). When a DSB occurs within or between direct repeats, resection can expose complementary strands in each repeat that anneal to form a deletion product. (b) SSA between repeats on separate chromosomes can produce translocations.


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Further Reading

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Rowley JD, Le Beau MM and Rabbitts TH (eds) (2015) Chromosomal Translocations and Genome Rearrangements in Cancer, 1st edn. New York, NY: Springer.

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Nickoloff, Jac A(May 2017) Mechanisms of Chromosome Translocations in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026853]