title: 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.
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. a1holland@ucsd.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Holland
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D020090:Chromosome Segregation / Q000235:genetics*; D004261:DNA Replication; D018628:Gene Dosage; D015321:Gene Rearrangement; D015894:Genome, Human; D042822:Genomic Instability; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008938:Mitosis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology