Valle-Inclan, Jose Espejo;
De Noon, Solange;
Trevers, Katherine;
Elrick, Hillary;
van Belzen, Ianthe AEM;
Zumalave, Sonia;
Sauer, Carolin M;
... Cortes-Ciriano, Isidro; + view all
(2025)
Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution.
Cell
, 188
(2)
pp. 352-370.
10.1016/j.cell.2024.12.005.
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Abstract
Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.
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