Der Pathologe

, Volume 39, Issue 2, pp 139–145 | Cite as

Pathogenese und genetischer Hintergrund des Osteosarkoms

Aktuelle Konzepte und Entwicklungen
Schwerpunkt: Knorpel, Knochen, Chorda – Molekulare Pathologie


Osteosarkome sind genetische komplexe Tumoren, deren Ursprungszelle und molekulargenetische Pathogenese noch weitgehend unbekannt sind. Trotz intensiver multimodaler Therapieprotokolle überleben nur etwa zwei Drittel der Patienten die Erkrankung, was zumindest teilweise auf die früh im Verlauf auftretende chromosomale Instabilität und die hierdurch bedingte inter- und intratumorale Heterogenität bedingt sein dürfte. In dieser Übersichtsarbeit wird der aktuelle Forschungsstand beim Osteosarkom mit speziellem Fokus auf exom- und genomweite Sequenzieranalysen dargestellt und die Auswirkungen auf mögliche Therapiekonzepte diskutiert.


Osteosarkom Chromothripsis Kopienzahlveränderungen BRCAness Checkpointinhibitoren 

Pathogenesis and genetics of osteosarcoma

Current concepts and developments


Osteosarcomas are genetically complex tumours for which the cell of origin and the molecular pathogenesis are still poorly understood. Despite intensive multimodal treatment protocols only two thirds of patients currently survive the disease which is at least partly due to the early occurring chromosomal instability resulting in marked inter- and intratumoral heterogeneity. This review article outlines the current state of osteosarcoma research with a particular focus on exome- and genome-wide sequencing analyses and potential impacts on new therapeutic opportunities.


Osteosarcoma Chromothripsis Copy number alterations BRCAness Checkpoint inhibitors 



Der Autor wurde unterstützt von der Stiftung des Basler Knochentumor-Referenzzentrums, der Gertrude von Meissner Stiftung, der Susy-Rückert Gedächtnis-Stiftung, der Nora van Meeuwen-Häfliger Stiftung sowie der Stiftung für krebskranke Kinder, Regio Basiliensis.

Einhaltung ethischer Richtlinien


D. Baumhoer gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.


  1. 1.
    Abkevich V, Timms KM, Hennessy BT et al (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776–1782CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Baca SC, Prandi D, Lawrence MS et al (2013) Punctuated evolution of prostate cancer genomes. Cell 153:666–677CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Baumhoer D (2017) Hereditary bone tumors. Pathologe 38:179–185CrossRefPubMedGoogle Scholar
  4. 4.
    Behjati S, Tarpey PS, Haase K et al (2017) Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat Commun 8:15936CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bielack SS, Kempf-Bielack B, Delling G 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 20:776–790CrossRefPubMedGoogle Scholar
  6. 6.
    Bielack SS, Smeland S, Whelan JS et al (2015) Methotrexate, Doxorubicin, and Cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade Osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 Good Response Randomized Controlled Trial. J Clin Oncol 33:2279–2287CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Birkbak NJ, Wang ZC, Kim JY et al (2012) Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2:366–375CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Burns MB, Temiz NA, Harris RS (2013) Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet 45:977–983CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cavenee WK, Bogler O, Hadjistilianou T et al (2013) Retinoblastoma syndrome. In: Fletcher C, Bridge J, Hogendoorn P, Mertens F (Hrsg) WHO classification of tumours of soft tissue and bone. IARC, Lyon, S 388–390Google Scholar
  10. 10.
    Chen X, Bahrami A, Pappo A et al (2014) Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7:104–112CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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):eaaf8399. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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 8:48794–48806CrossRefPubMedGoogle Scholar
  13. 13.
    Khong HT, Restifo NP (2002) Natural selection of tumor variants in the generation of „tumor escape“ phenotypes. Nat Immunol 3:999–1005CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kovac M, Blattmann C, Ribi S et al (2015) Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun 6:8940CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Li FP, Fraumeni JF, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358–5362PubMedGoogle Scholar
  16. 16.
    Lu L, Jin W, Liu H et al (2014) RECQ DNA helicases and osteosarcoma. Adv Exp Med Biol 804:129–145CrossRefPubMedGoogle Scholar
  17. 17.
    Malkin D (2013) Li-Fraumeni syndrome. In: Fletcher C, Bridge J, Hogendoorn P, Mertens F (Hrsg) WHO classification of tumours of soft tissue and bone. IARC, Lyon, S 379–381Google Scholar
  18. 18.
    Moriarity BS, Otto GM, Rahrmann EP et al (2015) A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nat Genet 47:615–624CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nik-Zainal S, Alexandrov LB, Wedge DC et al (2012) Mutational processes molding the genomes of 21 breast cancers. Cell 149:979–993CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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 USA 111:E5564–E5573CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Popova T, Manie E, Rieunier G et al (2012) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454–5462CrossRefPubMedGoogle Scholar
  22. 22.
    Ratti C, Botti L, Cancila V et al (2017) Trabectedin overrides osteosarcoma differentiative block and reprograms the tumor immune environment enabling effective combination with immune checkpoint inhibitors. Clin Cancer Res 23(17):5149–5161CrossRefPubMedGoogle Scholar
  23. 23.
    Ribi S, Baumhoer D, Lee K et al (2015) TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome. Oncotarget 6:7727–7740CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ripperger T, Bielack SS, Borkhardt A et al (2017) Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet A 173:1017–1037CrossRefPubMedGoogle Scholar
  25. 25.
    Rosenberg AE, Cleton-Jansen A‑M, De Pinieux G et al (2013) Conventional osteosarcoma. In: Fletcher C, Bridge J, Hogendoorn P, Mertens F (Hrsg) WHO classification of tumours of soft tissue and bone. IARC Press, Lyon, S 282–288Google Scholar
  26. 26.
    Roth A, Khattra J, Yap D et al (2014) PyClone: statistical inference of clonal population structure in cancer. Nat Methods 11:396–398CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Salinas-Souza C, De Andrea C, Bihl M et al (2015) GNAS mutations are not detected in parosteal and low-grade central osteosarcomas. Mod Pathol 28:1336–1342CrossRefPubMedGoogle Scholar
  28. 28.
    Savage SA, Mirabello L, Wang Z et al (2013) Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet 45:799–803CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Smida J, Baumhoer D, Rosemann M et al (2010) Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma. Clin Cancer Res 16:4256–4267CrossRefPubMedGoogle Scholar
  30. 30.
    Stephens PJ, Greenman CD, Fu B et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Watkins JA, Irshad S, Grigoriadis A et al (2014) Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 16:211CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH 2017

Authors and Affiliations

  1. 1.Knochentumor-Referenzzentrum am Institut für PathologieUniversitätsspital Basel, Universität BaselBaselSchweiz

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