Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms

Cell Rep. 2012 Jun 28;1(6):648-55. doi: 10.1016/j.celrep.2012.05.009. Epub 2012 Jun 15.


Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyze the genomes of ten patients with congenital disease who were preselected to carry complex chromosomal rearrangements with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint junctions indicates that break repair involves nonhomologous or microhomology-mediated end joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred base pairs and several megabases. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template switching. Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chromosome Breakage
  • Chromosome Deletion
  • Chromosome Duplication / genetics
  • Chromosomes, Human / genetics*
  • Cluster Analysis
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair / genetics*
  • DNA Replication / genetics
  • Gene Rearrangement / genetics*
  • Genome, Human / genetics
  • Humans
  • Molecular Sequence Data

Associated data

  • GEO/GSE37906