Genomics and the Immune Landscape of Osteosarcoma
Abstract
Conventional osteosarcoma (OS) is a high-grade intraosseous malignancy with production of osteoid matrix; however, a deeper dive into the underlying genetics reveals genomic complexity and instability that result in significant tumor heterogeneity. While early karyotyping studies demonstrated aneuploidy with chromosomal complexity and structural rearrangements, further investigations have identified few recurrent genetic alterations with the exception of the tumor suppressors TP53 and RB1. More recent studies utilizing next-generation sequencing (NGS; whole-exome sequencing, WES; and whole-genome sequencing, WGS) reveal a genomic landscape predominantly characterized by somatic copy number alterations rather than point/indel mutations. Despite its genomic complexity, OS has shown variable immune infiltrate and limited immunogenicity. In the current chapter, we review the hallmarks of OS genomics across recent NGS studies and the immune profile of OS including a large institutional cohort of OS patients with recurrent and metastatic disease. Understanding the genomic and immune landscape of OS may provide opportunities for translation in both molecularly targeted therapies and novel immuno-oncology approaches.
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The immunosuppressive mechanisms in osteosarcoma include highly mutated and rearranged osteosarcoma genome may not generate sufficient neoantigens to elicit an immune response, aneuploidy and copy number changes alterations, and deregulation of tumor-intrinsic immunosuppressive pathways such as IFNG, MAPK/PI3K/mTOR, and JAK/STAT signal pathways.
“The immunosuppressive mechanisms in osteosarcoma, including (1) Highly mutated and rearranged osteosarcoma genome may not generate sufficient neoantigens to elicit an immune response, (2) Aneuploidy and copy number changes alterations and (3) Deregulation of tumor-intrinsic immunosuppressive pathways such as IFNG, MAPK/PI3K/mTOR, and JAK/STAT signal pathways [76].”
From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [76]
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Deficiency of nucleotide excision repair explains mutational signature observed in cancerPreprint
Jager, M., Blokzijl, F., Kuijk, E., Bertl, J., Vougioukalaki, M., Janssen, R., Besselink, N. J. M., Boymans, S., de Ligt, J., Pedersen, J. S., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/221168 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Advancing therapy for osteosarcoma
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Advances on immunotherapy for osteosarcoma
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“…mutated and rearranged osteosarcoma genome may not generate sufficient neoantigens to elicit an immune response, (2) Aneuploidy and copy number changes alterations and (3) Deregulation of tumor-intrinsic immunosuppressive pathways such as IFNG, MAPK/PI3K/mTOR, and JAK/STAT signal pathways [76].”
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Current Status and Prospects of Targeted Therapy for Osteosarcoma
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Anlotinib for Recurrent or Metastatic Primary Malignant Bone Tumor: A Multicenter, Single-Arm Trial
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Children's Oncology Group's 2023 blueprint for research: Bone tumors
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Lin, Z., He, Y., Wu, Z., Yuan, Y., Li, X., & Luo, W. (2023) · Scientific Reports · doi:10.1038/s41598-023-42053-w · Cited by 19 · see citing works
Prognostic and immunological significance of an M1 macrophage-related gene signature in osteosarcoma
Mao, X., Song, F., Jin, J., Zou, B., Dai, P., Sun, M., Xu, W., Wang, L., & Kang, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1202725 · Cited by 16 · see citing works
A Comprehensive Understanding of the Genomic Bone Tumor Landscape: A Multicenter Prospective Study
Xie, X., Bian, Y., Li, H., Yin, J., Tian, L., Jiang, R., Zeng, Z., Shi, X., Lei, Z., Hou, C., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.835004 · Cited by 15 · see citing works
Zhang, Z., Zhang, J., Duan, Y., Li, X., Pan, J., Wang, G., & Shen, B. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1026701 · Cited by 16 · see citing works
Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics
Shu, Y., Peng, J., Feng, Z., Hu, K., Li, T., Zhu, P., Cheng, T., & Liang, H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.941724 · Cited by 15 · see citing works
Prognostic biomarkers correlated with immune infiltration in non‐small cell lung cancer
Xu, F., Cui, W., Liu, C., Feng, F., Liu, R., Zhang, J., & Sun, C. (2022) · FEBS Open Bio · doi:10.1002/2211-5463.13501 · Cited by 14 · see citing works
Naringenin induces ferroptosis in osteosarcoma cells through the STAT3-MGST2 signaling pathway
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Tang, H., Liu, S., Luo, X., Sun, Y. H., Li, X., Luo, K., Liao, S., Li, F., Liang, J., Zhan, X., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1150588 · Cited by 12 · see citing works
Zhu, J., Yuan, J., Arya, S., Zhi, D., Liu, X., & Jia, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1265098 · Cited by 13 · see citing works
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CYFIP1 coordinate with RNMT to induce osteosarcoma cuproptosis via AURKAIP1 m7G modification
Lin, Z., Wu, Z., He, Y., Li, X., & Luo, W. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01127-3 · Cited by 10 · see citing works
Osteoimmunology in bone malignancies: a symphony with evil
Song, C., Tong, T., Dai, B., Zhu, Y., Chen, E., Zhang, M., & Zhang, W. (2024) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2024.09.001 · Cited by 9 · see citing works
Osei-Hwedieh, D. O., Sedlacek, A. L., Hernandez, L. M., Agyekum-Yamoah, A., Iyer, S. G., Weiss, K. R., & Binder, R. J. (2023) · JCI Insight · doi:10.1172/jci.insight.170324 · Cited by 9 · see citing works
Hong, J., Li, Q., Wang, X., Li, J., Ding, W., Hu, H., & He, L. (2022) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.24501 · Cited by 9 · see citing works
Jiang, M., Jike, Y., Gan, F., Li, J., Hu, Y., Xie, M., Liu, K., Qin, W., & Bo, Z. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/9942014 · Cited by 8 · see citing works
RetractedDifferential gene expression analysis for osteosarcoma lung metastases
Liu, F., Pang, X., Yu, Z., & Wang, K. (2021) · Cancer Biomarkers · doi:10.3233/cbm-210232 · Cited by 7 · see citing works
MFNG is an independent prognostic marker for osteosarcoma
Gao, Y., Luo, L., Qu, Y., & Zhou, Q. (2023) · European journal of medical research · doi:10.1186/s40001-023-01139-x · Cited by 7 · see citing works
Current Advances in the Science of Osteosarcoma
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Tarone, L., Iacoviello, A., Lorenzo, A. D., Verta, R., Cossu, C., Conti, L., Cavallo, F., & Riccardo, F. (2025) · Cancers · doi:10.3390/cancers17233846 · Cited by 8 · see citing works
Targeting RBM39 suppresses tumor growth and sensitizes osteosarcoma cells to cisplatin
Wang, J., Zheng, L., Chen, W., Zhang, X., Lv, D., Zeng, C., Zhang, C., Zhang, R., Kang, T., & Zhong, L. (2024) · Oncogene · doi:10.1038/s41388-024-03242-7 · Cited by 7 · see citing works
Pediatric and Young Adult Image-Guided Percutaneous Bone Biopsy—A New Standard of Care?
Cooke‐Barber, J., Brungardt, J. G., Sorger, M., Pressey, J. G., Turpin, B. K., Nagarajan, R., Szabo, S., Sorger, J. I., Johnson, N. D., & Dasgupta, R. A. (2023) · Annals of Surgical Oncology · doi:10.1245/s10434-023-13097-z · Cited by 6 · see citing works
Osteosarcoma’s genetic landscape painted by genes’ mutations
Urban, W., Krzystańska, D., Piekarz, M., Nazar, J., & Jankowska, A. (2023) · Acta Biochimica Polonica · doi:10.18388/abp.2020_6869 · Cited by 5 · see citing works
Lu, Y., Cao, N., Zhao, M., Zhang, G., Zhang, Q., & Wang, L. (2024) · Scientific Reports · doi:10.1038/s41598-024-60539-z · Cited by 5 · see citing works
Construction and Validation of an Autophagy-Related Prognostic Model for Osteosarcoma Patients
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Osteosarcoma-Associated Immune Genes as Potential Immunotherapy and Prognosis Biomarkers
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Bibliometric analysis and visualisation of research hotspots and frontiers on omics in osteosarcoma
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PSAT1 inhibits ferroptosis in osteosarcoma cells by activating the Xct/GPX4 signaling axis
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Identification of telomere-related gene subtypes and prognostic signatures in osteosarcoma
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Construction of an immune prediction model for osteosarcoma based on coagulation-related genes
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Additional file 2 of MFNG is an independent prognostic marker for osteosarcoma
Gao, Y., Luo, L., Qu, Y., & Zhou, Q. (2023) · Figshare · doi:10.6084/m9.figshare.23788295
Additional file 1 of MFNG is an independent prognostic marker for osteosarcoma
Gao, Y., Luo, L., Qu, Y., & Zhou, Q. (2023) · Figshare · doi:10.6084/m9.figshare.23788292
Additional file 4 of MFNG is an independent prognostic marker for osteosarcoma
Gao, Y., Luo, L., Qu, Y., & Zhou, Q. (2023) · Figshare · doi:10.6084/m9.figshare.23788301
Additional file 3 of MFNG is an independent prognostic marker for osteosarcoma
Gao, Y., Luo, L., Qu, Y., & Zhou, Q. (2023) · Figshare · doi:10.6084/m9.figshare.23788298
Xu, Y., Du, L., Han, B., Wang, Y., Fei, J., Xia, K., Zhai, Y., & Yu, Z. (2023) · Figshare · doi:10.6084/m9.figshare.23803040
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Research on Pediatric Oncology
Metts, J. L., Raikar, S. S., Patel, K., Armstrong, A. E., & Dhir, A. (2026) · Springer eBooks · doi:10.1007/978-3-032-19175-5_26
Zhang, L., Zhou, Y., Yan, S., Zhang, X., Xu, T., Wang, X., Zhang, X., An, W., Xing, Y., & Song, Y. (2026) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2026179
- Authors
- Wu, C.-C., & Livingston, J. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Livingston, J. Andrew
- Venue
- Advances in Experimental Medicine and Biology
- Publisher
- Springer International Publishing
- Published
- 2020
- Volume
- 1258
- Pages
- 21-36
- ISSN
- 0065-2598 (ISSN-L)
- 2214-8019
- OpenAlex
- W3048320969
- Cited by
- 58
- References
- 83
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 16 · 2022: 11 · 2021: 8 · 2020: 1
- FWCI
- 62.06
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Advances in experimental medicine and biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- osteosarcoma, cancer genomics, tumor immune microenvironment, tumor heterogeneity, somatic copy number alterations, TP53, RB1, aneuploidy, metastatic osteosarcoma, immunogenicity, cancer immunotherapy, targeted therapy
- MeSH terms
- Bone Neoplasms, Humans, Mutation, Osteosarcoma, Genome, Human, Genomics, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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