Key Points
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Translocations that create neomorphic fusion genes occur in both lymphoid malignancies and solid tumours.
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A large number of translocations do not encode fusion genes and may not contribute to malignancy.
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Translocations frequently contain complex, clustered sequence rearrangements, similar to chromothrypsis, and may also contain genetic material from several different chromosomes.
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Many translocations arise as a consequence of 'classical' or 'alternative' pathways of non-homologous end-joining.
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Mammalian cells have regulatory systems to bias DNA repair towards repair pathways that are less likely to contribute to translocation.
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Frequency of DNA breakage is the metric that best predicts the likelihood of a particular genomic site being involved in a translocation.
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Therapeutic intervention to reduce translocation frequency is a potential mechanism for reducing the risk of cancer.
Abstract
Fusion genes that are caused by chromosome translocations have been recognized for several decades as drivers of deregulated cell growth in certain types of cancer. In recent years, oncogenic fusion genes have been found in many haematological and solid tumours, demonstrating that translocations are a common cause of malignancy. Sequencing approaches have now confirmed that numerous, non-clonal translocations are a typical feature of cancer cells. These chromosome rearrangements are often highly complex and contain DNA sequence from multiple genomic sites. The factors and pathways that promote translocations are becoming clearer, with non-homologous end-joining implicated as a key source of genomic rearrangements.
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Acknowledgements
S.F.B. is a recipient of NCI R00 award RCA160574A. A.N. was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the Center for Cancer Research, and by a Department of Defense grant (BC102335).
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Glossary
- Non-homologous end-joining
-
(NHEJ). Joining of DNA double-strand breaks without extensive sequence homology by ligation of DNA ends.
- Chromothrypsis
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A highly complex chromosome rearrangement event characterized by extensive re-assortment of genetic fragments from one or more chromosomes.
- Break-induced replication
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(BIR). A modified homology-based repair pathway in which a broken DNA end is repaired by copying a large amount of sequence from an undamaged homologous partner, potentially leading to copying of the entire homologous sequence from the site of damage to the end of the chromosome.
- Non-allelic homologous recombination
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(NAHR). Recombination between repetitive regions at different genomic sites that leads to chromosome rearrangements, as seen in genetic diseases such as Charcot–Marie–Tooth syndrome.
- Class switch recombination
-
(CSR). A region-specific deletional recombination reaction that replaces one switch region with another. This allows the production of different immunoglobulin isotypes.
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Bunting, S., Nussenzweig, A. End-joining, translocations and cancer. Nat Rev Cancer 13, 443–454 (2013). https://doi.org/10.1038/nrc3537
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DOI: https://doi.org/10.1038/nrc3537
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