Dataset Information

Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma.

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.

SUBMITTER: Kinnaman MD

PROVIDER: S-EPMC9881990 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma.

Kinnaman Michael D MD Zaccaria Simone S Makohon-Moore Alvin A Arnold Brian B Levine Max M Gundem Gunes G Ossa Juan E Arango JEA Glodzik Dominik D Rodríguez-Sánchez M Irene MI Bouvier Nancy N Li Shanita S Stockfisch Emily E Dunigan Marisa M Cobbs Cassidy C Bhanot Umesh U You Daoqi D Mullen Katelyn K Melchor Jerry J Ortiz Michael V MV O'Donohue Tara T Slotkin Emily E Wexler Leonard H LH Dela Cruz Filemon S FS Hameed Meera M Glade Bender Julia L JL Tap William D WD Meyers Paul A PA Papaemmanuil Elli E Kung Andrew L AL Iacobuzio-Donahue Christine A CA

bioRxiv : the preprint server for biology 20230124

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 ...[more]

PMID: 36711976

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Project description:Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease.SignificanceThe chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.

Dataset Information

Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma.

Publications

Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma.

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