Massive genomic rearrangement acquired in a single catastrophic event during cancer development
Stephens PJ., Greenman CD., Fu B., Yang F., Bignell GR., Mudie LJ., Pleasance ED., Lau KW., Beare D., Stebbings LA., McLaren S., Lin ML., McBride DJ., Varela I., Nik-Zainal S., Leroy C., Jia M., Menzies A., Butler AP., Teague JW., Quail MA., Burton J., Swerdlow H., Carter NP., Morsberger LA., Iacobuzio-Donahue C., Follows GA., Green AR., Flanagan AM., Stratton MR., Futreal PA., Campbell PJ.
Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%-3% of all cancers, across many subtypes, and is present in ∼25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer. PaperClip: © 2011 Elsevier Inc.