The DOI matches its Crossref record; 77 of the 78 references it cites were found in a registry or an index.
Genome-Informed Targeted Therapy for Osteosarcoma
Open accessAbstract
Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. Significance: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for “genome-matched” therapies, demonstrating the utility of a targeted genome-informed approach. This article is highlighted in the In This Issue feature, p. 1
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“This genomic complexity has long been interpreted as a sign of chromosomal instability but emerging data suggest that the mechanisms triggering complexity are active early in the process of malignant transformation 35,37 .”
From Osteosarcoma (2022) · cites this paper as [35]
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“These rearrangements give rise to genome-wide copy number alterations, usually dominated by copy number loss, including of PTEN and CDKN2A/B, but with recurrent amplifications of MYC, VEGFA and CCNE1 (ref.35 ).”
From Osteosarcoma (2022) · cites this paper as [35]
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“Of note, the resulting complex genomes are subsequently maintained with some fidelity, even from diagnosis to relapse 35,37 .”
From Osteosarcoma (2022) · cites this paper as [35]
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“the paitients with metastatic disease either at diagnosis or at the time of recurrence portends a dismal prognosis with 5-year survival of only 20-30% [8].”
From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [8]
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“Copy number amplifications of potentially targetable genes seemed to predict sensitivity to specific agents 35 ; however, subsequent work has shown that the picture is much more complicated 9 .”
From Osteosarcoma (2022) · cites this paper as [35]
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“Recurrent CDK4 alterations have been described in osteosarcoma 35 .”
From Osteosarcoma (2022) · cites this paper as [35]
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“Furthermore, current molecular research continues to classify osteosarcomas not by histological appearance via classical osteosarcoma pathological descriptions but by proteo-genomic drivers of disease that provide further insight into disease biology and may have both prognostic and therapeutic implications 35 .”
From Osteosarcoma (2022) · cites this paper as [35]
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Molecular Biology of Osteosarcoma
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Metadata
- Authors
- Sayles, L. C., Breese, M. R., Koehne, A. L., Leung, S. G., Lee, A. G., Liu, H.-Y., Spillinger, A., Shah, A. T., Tanasa, B., Straessler, K., Hazard, F. K., Spunt, S. L., Marina, N., Kim, G. E., Cho, S.-J., Avedian, R. S., Mohler, D. G., Kim, M.-O., DuBois, S. G., Hawkins, D. S., & Sweet-Cordero, E. A.
- Affiliations
- University of California, San Francisco (US)
- 1Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, California.
- Stanford Medicine (US)
- Harvard University (US)
- Seattle Children's Hospital (US)
- ORCID
- Venue
- Cancer Discovery
- Published
- 2019-01-01
- Volume
- 9
- Issue
- 1
- Pages
- 46-63
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC7134333
- OpenAlex
- W2892650455
- Cited by
- 452
- References
- 78
- Citations by year
- 2026: 48 · 2025: 59 · 2024: 67 · 2023: 84 · 2022: 63 · 2021: 63 · 2020: 52 · 2019: 14
- FWCI
- 24.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | National Institutes of Health (NIH) (S10OD018220, P30CA082103, 2T32OD011121-11, R25 CA180993-02)
- Hyundai Motor Group | Hyundai Motor America | Hyundai Hope On Wheels (Hope On Wheels)
- Stanford University School of Medicine (Stanford School of Medicine, Stanford University) (Morgridge Scholar Grant)
- St. Baldrick's Foundation (Team Clarkie)
- CureSearch for Children's Cancer
- Sarcoma Foundation of America (SFA)
- Topics
- Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- osteosarcoma, somatic copy number alterations, structural rearrangement, targeted therapy, patient-derived xenografts, copy number amplification, gene expression changes, oncogenic drivers
- MeSH terms
- Whole Genome Sequencing, Animals, Bone Neoplasms, Humans, Osteosarcoma, Sequence Analysis, RNA, Xenograft Model Antitumor Assays, Genomics, Mice, Genomic Structural Variation, DNA Copy Number Variations, Molecular Targeted Therapy
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