Chromothripsis: A Catastrophic Driver of Genomic Instability

The classical model of genomic instability portrays cancer evolution as a gradual, stepwise accumulation of mutations over decades. Chromothripsis, first described in 2011, challenged this paradigm by demonstrating that tens to hundreds of clustered chromosomal rearrangements can arise within a single catastrophic event, effectively compressing prolonged evolutionary change into one cell cycle. This review synthesises current understanding of chromothripsis as a major driver of genomic catastrophe. We describe its defining genomic hallmarks and the mechanisms proposed to initiate chromothripsis, with particular emphasis on the micronucleus pathway, alongside alternative mechanisms involving breakage–fusion–bridge cycles and replication stress. Across these pathways, extensive chromosome fragmentation followed by error-prone repair can generate highly rearranged derivative chromosomes, including neochromosomes. The biological consequences are dichotomous: although most affected cells succumb to cell death, rare survivors can acquire multiple oncogenic alterations simultaneously, including oncogene amplification, tumor suppressor loss, and neomorphic gene fusions, thereby accelerating malignant transformation and therapeutic resistance. We survey chromothripsis across a broad spectrum of malignancies and congenital disorders. The review critically evaluates the prognostic significance of chromothripsis and emerging therapeutic implications, including potential vulnerabilities to PARP and ATR inhibition, and immune checkpoint blockade. Finally, we highlight unresolved questions and priorities for future research. Collectively, chromothripsis compels a fundamental reappraisal of genomic instability: rather than being exclusively a gradual process, it can occur as a sudden genomic catastrophe that reshapes the genome in a single event, with profound implications for biomarker discovery, cancer evolution, and precision oncology.