Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development
Philip J. Stephens, Chris D. Greenman, Beiyuan Fu, Fengtang Yang, Graham R. Bignell, Laura J. Mudie, Erin D. Pleasance, King Wai Lau, David Beare, Lucy A. Stebbings, Stuart McLaren, Meng-Lay Lin, David J. McBride, Ignacio Varela, Serena Nik-Zainal, Catherine Leroy, Mingming Jia, Andrew Menzies, Adam P. Butler, Jon W. Teague, Michael A. Quail, John Burton, Harold Swerdlow, Nigel P. Carter, Laura A. Morsberger, Christine Iacobuzio-Donahue, George A. Follows, Anthony R. Green, Adrienne M. Flanagan, Michael R. Stratton, P. Andrew Futreal, Peter J. Campbell
Highlights
2%–3% cancers show 10–100 s of rearrangements localized to specific genomic regions
Genomic features imply chromosome breaks occur in one-off crisis (“chromothripsis”)
Found across all tumor types, especially common in bone cancers (up to 25%)
Can generate several genomic lesions with potential to drive cancer in single event
Summary
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.
