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

Andrew J. Holland, Don W. Cleveland

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1630-1638
Number of pages9
JournalNature medicine
Volume18
Issue number11
DOIs
StatePublished - Nov 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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