Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development

TLDR

Cancer is driven by somatic point mutations and chromosomal rearrangements that are traditionally thought to accumulate gradually. The study aims to characterize chromothripsis, a catastrophic event that generates tens to hundreds of genomic rearrangements in a single cellular crisis. Next‑generation sequencing was employed to identify and analyze chromothripsis events. Chromothripsis produces oscillating copy‑number patterns across one or few chromosomes, occurs in 2–3% of cancers (≈25% of bone cancers), can generate multiple oncogenic lesions, and indicates that most rearrangements arise in a single catastrophic event.

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.PaperClip/cms/asset/11160b8f-e385-4dd3-bf95-502960456925/mmc8.mp3Loading ...(mp3, 2.86 MB) Download audio