Mechanisms underpinning osteosarcoma genome complexity and evolution

Espejo Valle-Inclan, J.; De Noon, S.; Trevers, K.; Elrick, H.; Tanguy, M.; Butters, T.; Muyas, F.; Amary, F.; Tirabosco, R.; Giess, A.; Sosinky, A.; Elgar, G.; Flanagan, A. M.; Cortes-Ciriano, I.

doi:10.1101/2023.12.29.573403

bioRxiv · 10.1101/2023.12.29.573403

Mechanisms underpinning osteosarcoma genome complexity and evolution

Espejo Valle-Inclan, J.·De Noon, S.·Trevers, K.·Elrick, H.·Tanguy, M.·Butters, T.·Muyas, F.·Amary, F.·Tirabosco, R.·Giess, A.·Sosinky, A.·Elgar, G.·Flanagan, A. M.·Cortes-Ciriano, I.

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Abstract

Osteosarcoma is the most common primary cancer of bone with a peak incidence in children and young adults. Despite progress, the genomic aberrations underpinning osteosarcoma evolution remain poorly understood. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of tumours. Chromothripsis drives the acquisition of oncogenic mutations and generates highly unstable derivative chromosomes, the evolution of which drives clonal diversification and intra-tumour heterogeneity. In addition, we report a novel mechanism, loss-translocation-amplification (LTA) chromothripsis, which mediates rapid malignant transformation and punctuated evolution in about half of paediatric and adult high-grade osteosarcomas. Specifically, a single double-strand break triggers concomitant TP53 inactivation and segmental amplifications, often amplifying oncogenes to high copy numbers in extrachromosomal circular DNA elements through breakage-fusion-bridge cycles involving multiple chromosomes. LTA chromothripsis is detected at low frequency in soft-tissue sarcomas, but not in epithelial cancers, including those driven by TP53 mutation. Finally, we identify genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.

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Espejo Valle-Inclan, J., De Noon, S., Trevers, K., Elrick, H., Tanguy, M., Butters, T., Muyas, F., Amary, F., Tirabosco, R., Giess, A., Sosinky, A., Elgar, G., Flanagan, A. M., Cortes-Ciriano, I.. 2023-12-29. Mechanisms underpinning osteosarcoma genome complexity and evolution. https://doi.org/10.1101/2023.12.29.573403

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