Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements

Abstract

Next-generation sequencing of DNA from human tumors or individuals with developmental abnormalities has led to the discovery of a process we term chromoanagenesis, in which large numbers of complex rearrangements occur at one or a few chromosomal loci in a single catastrophic event. Two mechanisms underlie these rearrangements, both of which can be facilitated by a mitotic chromosome segregation error to produce a micronucleus containing the chromosome to undergo rearrangement. In the first, chromosome shattering (chromothripsis) is produced by mitotic entry before completion of DNA replication within the micronucleus, with a failure to disassemble the micronuclear envelope encapsulating the chromosomal fragments for random reassembly in the subsequent interphase. Alternatively, locally defective DNA replication initiates serial, microhomology-mediated template switching (chromoanasynthesis) that produces local rearrangements with altered gene copy numbers. Complex rearrangements are present in a broad spectrum of tumors and in individuals with congenital or developmental defects, highlighting the impact of chromoanagenesis on human disease.

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Figure 1: Mechanism for the creation of complex chromosomal rearrangements by NHEJ after chromosome shattering.
Figure 2: Mitotic errors produce micronuclei and subsequent chromoanagenesis.
Figure 3: Mechanism for complex chromosomal rearrangements as a result of FoSTes and MMBIR.
Figure 4: Chromoanagenesis may create oncogenic lesions.

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Acknowledgements

We apologize to all whose work was not cited because of space restrictions. This work was supported by a grant (GM29513) from the US National Institutes of Health to D.W.C., who receives salary support from the Ludwig Institute for Cancer Research. A.J.H. is supported by a Leukemia & Lymphoma Society special fellowship.

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Correspondence to Andrew J Holland or Don W Cleveland.

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Holland, A., Cleveland, D. Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med 18, 1630–1638 (2012). https://doi.org/10.1038/nm.2988

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