Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma

Kinnaman, M. D.; Zaccaria, S.; Makohon-Moore, A.; Arnold, B.; Levine, M.; Gundem, G.; Ossa, J. E. A.; Glodzik, D.; Sanchez, M. I. R.; Bouvier, N.; Li, S.; Stockfisch, E.; Dunigan, M.; Cobbs, C.; Bhanot, U.; You, D.; Ortiz, M. V.; O'Donohue, T.; Slotkin, E.; Wexler, L. H.; Cruz, F. S. D.; Hameed, M.; Bender, J. L. G.; Tap, W. D.; Meyers, P.; Papaemmanuil, E.; Kung, A. L.; Iacobuzio-Donahue, C. A.

doi:10.1101/2023.01.05.522765

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bioRxiv · 10.1101/2023.01.05.522765

Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma

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Abstract

Multiple large-scale tumor genomic profiling efforts have been undertaken in osteosarcoma, however, little is known about the spatial and temporal intratumor heterogeneity and how it may drive treatment resistance. We performed whole-genome sequencing of 37 tumor samples from eight patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. We identified subclonal copy number alterations in all but one patient. We observed that in five patients, a subclonal copy number clone from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clone in 6 out of 7 patients with more than one clone. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy number clones. Our study sheds light on intratumor heterogeneity and the potential drivers of treatment resistance in osteosarcoma. SignificanceSubclonal copy number clones emerged and dominated in relapsed osteosarcoma, with MYC gain/amplification being the defining characteristic in our cohort. Selective pressure from neoadjuvant chemotherapy revealed this clone at the time of primary resection, highlighting that genomic profiling at this time may identify clones that are selected for, or determine innate resistance to primary chemotherapy.

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Kinnaman, M. D., Zaccaria, S., Makohon-Moore, A., Arnold, B., Levine, M., Gundem, G., Ossa, J. E. A., Glodzik, D., Sanchez, M. I. R., Bouvier, N., Li, S., Stockfisch, E., Dunigan, M., Cobbs, C., Bhanot, U., You, D., Ortiz, M. V., O'Donohue, T., Slotkin, E., Wexler, L. H., Cruz, F. S. D., Hameed, M., Bender, J. L. G., Tap, W. D., Meyers, P., Papaemmanuil, E., Kung, A. L., Iacobuzio-Donahue, C. A.. 2023-01-06. Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma. https://doi.org/10.1101/2023.01.05.522765

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