Skip to main content
SpringerLink
Log in

Genomics and the Immune Landscape of Osteosarcoma

  • Chapter
  • First Online:
Current Advances in the Science of Osteosarcoma

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1258))

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alexandrov LB, Nik-Zainal S, Wedge DC et al (2013) Signatures of mutational processes in human cancer. Nature 500(7463):415–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bai J, Gao Z, Li X et al (2017) Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget 8(66):110693–110707

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bayram F, Bitgen N, Donmez-Altuntas H et al (2014) Increased genome instability and oxidative DNA damage and their association with IGF-1 levels in patients with active acromegaly. Growth Hormon IGF Res 24(1):29–34

    Article  CAS  Google Scholar 

  4. Behjati S, Tarpey PS, Haase K et al (2017) Recurrent mutation of IGF signaling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat Commun 8:ncomms15936

    Article  CAS  Google Scholar 

  5. Beroukhim R, Mermel CH, Porter D et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bielack SS, Kempf-Bielack B, Delling GN et al (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20:776–790

    Article  PubMed  Google Scholar 

  7. Blokzijl F, de Ligt J, Jager M et al (2016) Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538(7624):260–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bousquet M, Noirot C, Accadbled F et al (2016) Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations. Ann Oncol 27:738–744

    Article  CAS  PubMed  Google Scholar 

  9. Brogna S, Wen J (2009) Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol 16(2):107–113

    Article  CAS  PubMed  Google Scholar 

  10. Burgess MA, Bolejack V, Tine BAV et al (2017) Multicenter phase II study of pembrolizumab (P) in advanced soft tissue (STS) and bone sarcomas (BS): final results of SARC028 and biomarker analyses. J Clin Oncol 35:11008–11008

    Article  Google Scholar 

  11. Carter SL, Cibulskis K, Helman E et al (2012) Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 30(5):413–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Charoentong P, Finotello F, Angelova M et al (2017) Pan-cancer Immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep 18(1):248–262

    Article  CAS  PubMed  Google Scholar 

  13. Chen X, Bahrami A, Pappo A et al (2014) Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7:104–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen Y-J, Hakin-Smith V, Teo M et al (2006) Association of mutant TP53 with alternative lengthening of telomeres and favorable prognosis in glioma. Cancer Res 66:6473–6476

    Article  CAS  PubMed  Google Scholar 

  15. Coudray A, Battenhouse AM, Bucher P et al (2018) Detection and benchmarking of somatic mutations in cancer genomes using RNA-seq data. bioRxiv 2018:249219

    Google Scholar 

  16. Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer immunotherapy. Science 342(6165):1432–1433

    Article  CAS  PubMed  Google Scholar 

  17. Davoli T, Uno H, Wooten EC et al (2017) Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355(6322):pii:eaaf8399

    Article  CAS  Google Scholar 

  18. Dewhurst SM, McGranahan N, Burrell RA et al (2014) Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov 4(2):175–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Engert F, Kovac M, Baumhoer D et al (2017) Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics. Oncotarget 8(30):48794–48806

    Article  PubMed  Google Scholar 

  20. Flynn RL, Cox KE, Jeitany M et al (2015) Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347:273–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Forment JV, Kaidi A, Jackson SP (2012) Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 12(10):663–670

    Article  CAS  PubMed  Google Scholar 

  22. Gianferante DM, Mirabello L, Savage SA (2017) Germline and somatic genetics of osteosarcoma – connecting aetiology, biology and therapy. Nat Rev Endocrinol 13(8):480–491

    Article  CAS  PubMed  Google Scholar 

  23. He Y, de Castro LF, Shin MH et al (2015) p53 loss increases the osteogenic differentiation of bone marrow stromal cells. Stem Cells 33(4):1304–1319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang J, Wang L, Cong Z et al (2015) The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(−/−) murine model of ovarian cancer. Biochem Biophys Res Commun 463(4):551–556

    Article  CAS  PubMed  Google Scholar 

  25. Hugo W, Zaretsky JM, Sun L et al (2016) Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165(1):35–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jager M, Blokzijl F, Kuijk E et al (2019) Deficiency of global genome nucleotide excision repair explains mutational signature observed in cancer. Genome Res 29(7):1067–1077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jiao S, Xia W, Yamaguchi H et al (2017) PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 23:3711–3720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kager L, Zoubek A, Pötschger U et al (2003) Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 21:2011–2018

    Article  PubMed  Google Scholar 

  29. Kansara M, Teng MW, Smyth MJ et al (2014) Translational biology of osteosarcoma. Nat Rev Cancer 14(11):722–735

    Article  CAS  PubMed  Google Scholar 

  30. Keenan TE, Burke KP, Van Allen EM (2019) Genomic correlates of response to immune checkpoint blockade. Nat Med 25(3):389–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Killela PJ, Reitman ZJ, Jiao Y et al (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 110(15):6021–6026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Koirala P, Roth ME, Gill J et al (2016) Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci Rep 6:30093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kovac M, Blattmann C, Ribi S et al (2015) Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun 6:8940

    Google Scholar 

  34. Lastwika KJ, Wilson W 3rd, Li QK et al (2015) Control of PD-L1 expression by oncogenic activation of the AKT/mTOR pathway in non-small cell lung cancer. Cancer Res 76(2):227–238

    Article  PubMed  CAS  Google Scholar 

  35. Li Q, Rao RR, Araki K et al (2011) A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity 34(4):541–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li B, Severson E, Pignon JC et al (2016) Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol 17:174

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Li Y, Roberts ND, Weischenfeldt J et al (2017) Patterns of structural variation in human cancer. bioRxiv. https://doi.org/10.1101/181339v1

  38. Li YS, Liu Q, He HB et al (2019) The possible role of insulin-like growth factor-1 in osteosarcoma. Curr Probl Cancer 43(3):228–235

    Article  PubMed  Google Scholar 

  39. Maciejowski J, Li Y, Bosco N et al (2015) Chromothripsis and kataegis induced by telomere crisis. Cell 163:1641–1654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maciejowski J, de Lange T (2017) Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol 18(3):175–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McEachron TA, Triche TJ, Sorenson L et al (2018) Profiling targetable immune checkpoints in osteosarcoma. Onco Targets Ther 7(12):e1475873

    Google Scholar 

  42. Meyers PA, Heller G, Healey JH et al (1993) Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol 11:449–453

    Article  CAS  PubMed  Google Scholar 

  43. Miao D, Margolis CA, Vokes NI et al (2018) Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet 50(9):1271–1281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mirabello L, Troisi RJ, Savage SA (2009) Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 115:1531–1543

    Article  PubMed  Google Scholar 

  45. Mouw KW, Goldberg MS, Konstantinopoulos PA et al (2017) DNA damage and repair biomarkers of immunotherapy response. Cancer Discov 7(7):675–693

    Google Scholar 

  46. O’Brien TD, Jia P, Xia J et al (2015) Inconsistency and features of single nucleotide variants detected in whole exome sequencing versus transcriptome sequencing: a case study in lung cancer. Methods 83:118–127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Ock CY, Hwang JE, Keam B et al (2017) Genomic landscape associated with potential response to anti-CTLA-4 treatment in cancers. Nat Commun 8(1):1050

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Palmerini E, Agostinelli C, Picci P et al (2017) Tumoral immune-infiltrate (IF), PD-L1 expression and role of CD8/TIA-1 lymphocytes in localized osteosarcoma patients treated within protocol ISG-OS1. Oncotarget 8(67):111836–111846

    Article  PubMed  PubMed Central  Google Scholar 

  49. Perry JA, Kiezun A, Tonzi P et al (2014) Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci 111:E5564–E5573

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Petitjean A, Achatz MI, Borresen-Dale AL et al (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26(15):2157–2165

    Article  CAS  PubMed  Google Scholar 

  51. Rausch T, Jones David TW, Zapatka M et al (2012) Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148:59–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rickel K, Fang F, Tao J (2017) Molecular genetics of osteosarcoma. Bone 102:69–79

    Article  CAS  PubMed  Google Scholar 

  53. Roh W, Chen PL, Reuben A et al (2017) Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med 9(379):pii: eaah3560

    Article  CAS  Google Scholar 

  54. Sade-Feldman M, Jiao YJ, Chen JH et al (2017) Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun 8(1):1136

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Seplyarskiy VB, Soldatov RA, Popadin KY et al (2016) APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication. Genome Res 26(2):174–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sharma P, Hu-Lieskovan S, Wargo JA et al (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shen JK, Cote GM, Choy E et al (2014) Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res 2(7):690–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sun C, Mezzadra R, Schumacher TN (2018) Regulation and function of the PD-L1 checkpoint. Immunity 48(3):434–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tawbi HA, Burgess M, Bolejack V et al (2017) Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 18(11):1493–1501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Taylor AM, Shih J, Ha G et al (2018) Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33(4):676–689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. The Cancer Genome Atlas (2013) The cancer genome atlas pan-cancer analysis project. Nat Genet 45(10):1113–1120

    Article  CAS  Google Scholar 

  62. Thompson LH (2012) Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography. Mutat Res 751:158–246

    Article  CAS  PubMed  Google Scholar 

  63. Thorsson V, Gibbs DL, Brown SD et al (2018) The immune landscape of cancer. Immunity 48(4):812–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Turajlic S, Litchfield K, Xu H et al (2017) Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol 18(8):1009–1021

    Article  CAS  PubMed  Google Scholar 

  65. van Harn T, Foijer F, van Vugt M et al (2010) Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev 24(13):1377–1388

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Walkley CR, Qudsi R, Sankaran VG et al (2008) Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes Dev 22(12):1662–1676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wargo JA, Cooper ZA, Flaherty KT (2014) Universes collide: combining immunotherapy with targeted therapy for cancer. Cancer Discov 4(12):1377–1386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wellenstein MD, de Visser KE (2018) Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity 48(3):399–416

    Article  CAS  PubMed  Google Scholar 

  69. Werner H, Sarfstein R, LeRoith D et al (2016) Insulin-like growth factor 1 signaling axis meets p53 genome protection pathways. Front Oncol 6:159

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wilky BA, Trucco MM, Subhawong TK et al (2019) Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol 20(6):837–848

    Article  CAS  PubMed  Google Scholar 

  71. Wu CC, Beird HC, Livingston JA et al (2019) Immuno-genomic landscape of osteosarcoma. Nat Commun 11(1):1008

    Article  CAS  Google Scholar 

  72. Yakar S, Rosen CJ, Beamer WG et al (2002) Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 110(6):771–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yoshida K, Miki Y (2004) Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 95(11):866–871

    Article  CAS  PubMed  Google Scholar 

  74. Yoshihara K, Shahmoradgoli M, Martinez E et al (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612

    Article  PubMed  CAS  Google Scholar 

  75. Zhao X, Subramanian S (2017) Oncogenic pathways that affect antitumor immune response and immune checkpoint blockade therapy. Pharmacol Ther 181:76–84

    Article  PubMed  CAS  Google Scholar 

  76. Sansregret L, Vanhaesebroeck B, Swanton C (2018) Determinants and clinical implications of chromosomal instability in cancer. Nature Reviews Clinical Oncology 15 (3):139–150

    Google Scholar 

  77. Brown SD, Warren RL, Gibb EA et al (2014) Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Research 24 (5):743–750

    Google Scholar 

  78. Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348 (6230):69–74

    Google Scholar 

  79. Wunder JS, Gokgoz N, Parkes R et al(2005) TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study. Journal of Clinical Oncology 23 (7):1483–1490

    Google Scholar 

  80. Holland AJ, Cleveland DW (2009) Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nature Reviews Molecular Cell Biology 10 (7):478–487

    Google Scholar 

  81. Yang Y, Zhang Y, Qu X et al (2016) Identification of differentially expressed genes in the development of osteosarcoma using RNA-seq. Oncotarget 7 (52)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Chia-Chin Wu

  2. Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J. Andrew Livingston

  3. Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J. Andrew Livingston

Authors
  1. Chia-Chin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Andrew Livingston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Andrew Livingston .

Editor information

Editors and Affiliations

  1. Department of Pediatric Research Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Eugenie S. Kleinerman

  2. Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Richard Gorlick

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wu, CC., Livingston, J.A. (2020). Genomics and the Immune Landscape of Osteosarcoma. In: Kleinerman, E., Gorlick, R. (eds) Current Advances in the Science of Osteosarcoma. Advances in Experimental Medicine and Biology, vol 1258. Springer, Cham. https://doi.org/10.1007/978-3-030-43085-6_2

Download citation

Publish with us

Policies and ethics

Search

Navigation