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

Nat Med. 2012 Nov;18(11):1630-8. doi: 10.1038/nm.2988. Epub 2012 Nov 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Aberrations*
  • Chromosome Breakage
  • Chromosome Segregation / genetics*
  • DNA Replication
  • Gene Dosage
  • Gene Rearrangement*
  • Genome, Human
  • Genomic Instability
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mitosis
  • Neoplasms* / genetics
  • Neoplasms* / pathology