title: Massive genomic rearrangement acquired in a single catastrophic event during cancer development.
abstract: 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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Chris D
authors.initials: CD
authors.lastname: Greenman
authors.forename: Beiyuan
authors.initials: B
authors.lastname: Fu
authors.forename: Fengtang
authors.initials: F
authors.lastname: Yang
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Mudie
authors.forename: Erin D
authors.initials: ED
authors.lastname: Pleasance
authors.forename: King Wai
authors.initials: KW
authors.lastname: Lau
authors.forename: David
authors.initials: D
authors.lastname: Beare
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Stebbings
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaren
authors.forename: Meng-Lay
authors.initials: ML
authors.lastname: Lin
authors.forename: David J
authors.initials: DJ
authors.lastname: McBride
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.forename: Catherine
authors.initials: C
authors.lastname: Leroy
authors.forename: Mingming
authors.initials: M
authors.lastname: Jia
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.forename: Michael A
authors.initials: MA
authors.lastname: Quail
authors.forename: John
authors.initials: J
authors.lastname: Burton
authors.forename: Harold
authors.initials: H
authors.lastname: Swerdlow
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Carter
authors.forename: Laura A
authors.initials: LA
authors.lastname: Morsberger
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: George A
authors.initials: GA
authors.lastname: Follows
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D020223:Chromosome Painting; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*