Der Onkologe

, Volume 19, Issue 8, pp 629–634

Aktueller Stand der Molekularpathologie von Knochentumoren




Die morphologische Diagnose von Knochentumoren stellt oft eine Herausforderung dar. Molekularpathologisch sind bei der Routinediagnostik von Knochentumoren bisher zwei spezifische genetische Veränderungen von Bedeutung: zum einen die Detektion der EWSR1-Translokation bei Ewing-Sarkomen, zum anderen die GNAS1-Mutationsanalyse bei fibröser Dysplasie. Sensitivere und schnellere Techniken ermöglichen jedoch eine bessere Detektion von spezifischen genetischen Veränderungen bei Knochentumoren.

Ergebnisse und Schlussfolgerung

So lassen sich bei vielen anderen Knochentumoren spezifische Translokationen und Mutationen feststellen, mit denen sich in Zukunft die Diagnose anhand des morphologischen Bilds durch den molekularpathologischen Nachweis dieser spezifischen genetischen Veränderung unterstützen lässt. Manche Tumoren, wie z. B. das Osteosarkom, weisen jedoch eine generell hohe genetische Instabilität mit zahlreichen, nichtspezifischen genetischen Veränderungen auf.


Translokation Mutation Ewing-Sarkom Osteosarkom Chondrosarkom 

Current state of molecular pathology of bone tumors



The morphological diagnosis of bone tumors can often be challenging. In molecular pathology only two genetic aberrations are used in routine diagnostics of bone tumors: the detection of the EWSR1 translocation in Ewing’s sarcoma and the GNAS1 mutation analysis in fibrous dysplasia. Faster and more sensitive techniques allow the identification of specific genetic aberrations in many bone tumors.

Results and conclusion

This will help support the diagnosis of bone tumors by identification of these specific translocations and mutations with the help of molecular pathology. However, some tumors, such as osteosarcomas, show a high genetic instability without recurrent genetic abnormalities.


Translocation Mutation Ewing’s sarcoma Osteosarcoma Chondrosarcoma 


  1. 1.
    Amary MF, Bacsi K, Maggiani F et al (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343PubMedCrossRefGoogle Scholar
  2. 2.
    Choy E, Hornicek F, Macconaill L et al (2012) High-throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide-3-kinase and other oncogenes. Cancer 118:2905–2914PubMedCrossRefGoogle Scholar
  3. 3.
    Delattre O, Zucman J, Melot T et al (1994) The Ewing family of tumors–a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:294–299PubMedCrossRefGoogle Scholar
  4. 4.
    Errani C, Zhang L, Sung YS et al (2011) A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer 50:644–653PubMedCrossRefGoogle Scholar
  5. 5.
    Hallor KH, Staaf J, Jönsson G et al (2008) Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation. Br J Cancer 98:434–442PubMedCrossRefGoogle Scholar
  6. 6.
    Haroche J, Charlotte F, Arnaud L et al (2012) High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 120:2700–2703PubMedCrossRefGoogle Scholar
  7. 7.
    Haroche J, Cohen-Aubart F, Emile JF et al (2013) Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121:1495–1500PubMedCrossRefGoogle Scholar
  8. 8.
    Idowu BD, Al-Adnani M, O’donnell P et al (2007) A sensitive mutation-specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone. Histopathology 50:691–704PubMedCrossRefGoogle Scholar
  9. 9.
    Jedlicka P (2010) Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions. Int J Clin Exp Pathol 3:338–347PubMedGoogle Scholar
  10. 10.
    Jones KB, Piombo V, Searby C et al (2010) A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proc Natl Acad Sci U S A 107:2054–2059PubMedCrossRefGoogle Scholar
  11. 11.
    Ladanyi M, Gerald W (1994) Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Cancer Res 54:2837–2840PubMedGoogle Scholar
  12. 12.
    Le Deley MC, Delattre O, Schaefer KL et al (2010) Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 28:1982–1988CrossRefGoogle Scholar
  13. 13.
    Nowell PC, Hungerford DA (1962) Chromosome studies in human leukemia. IV. Myeloproliferative syndrome and other atypical myeloid disorders. J Natl Cancer Inst 29:911–931PubMedGoogle Scholar
  14. 14.
    Panagopoulos I, Mertens F, Isaksson M et al (2002) Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer 35:340–352PubMedCrossRefGoogle Scholar
  15. 15.
    Pansuriya TC, Van Eijk R, D’adamo P et al (2011) Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43:1256–1261PubMedCrossRefGoogle Scholar
  16. 16.
    Park HR, Jung WW, Bertoni F et al (2004) Molecular analysis of p53, MDM2 and H-ras genes in low-grade central osteosarcoma. Pathol Res Pract 200:439–445PubMedCrossRefGoogle Scholar
  17. 17.
    Pollandt K, Engels C, Kaiser E et al (2001) Gsalpha gene mutations in monostotic fibrous dysplasia of bone and fibrous dysplasia-like low-grade central osteosarcoma. Virchows Arch 439:170–175PubMedCrossRefGoogle Scholar
  18. 18.
    Presneau N, Shalaby A, YE H et al (2011) Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study. J Pathol 223:327–335PubMedCrossRefGoogle Scholar
  19. 19.
    Raskind WH, Conrad EU, Matsushita M (1996) Frequent loss of heterozygosity for markers on chromosome arm 10q in chondrosarcomas. Genes Chromosomes Cancer 16:138–143PubMedCrossRefGoogle Scholar
  20. 20.
    Sakamoto A, Oda Y, Iwamoto Y et al (2000) A comparative study of fibrous dysplasia and osteofibrous dysplasia with regard to Gsalpha mutation at the Arg201 codon: polymerase chain reaction-restriction fragment length polymorphism analysis of paraffin-embedded tissues. J Mol Diagn 2:67–72PubMedCrossRefGoogle Scholar
  21. 21.
    Sandberg AA, Bridge JA (2003) Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: osteosarcoma and related tumors. Cancer Genet Cytogenet 145:1–30PubMedCrossRefGoogle Scholar
  22. 22.
    Sankar S, Lessnick SL (2011) Promiscuous partnerships in Ewing’s sarcoma. Cancer Genet 204:351–365PubMedCrossRefGoogle Scholar
  23. 23.
    Schrage YM, Lam S, Jochemsen AG et al (2009) Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. J Cell Mol Med 13:2843–2852PubMedCrossRefGoogle Scholar
  24. 24.
    Sciot R, Dorfman H, Brys P et al (2000) Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group. Mod Pathol 13:1206–1210PubMedCrossRefGoogle Scholar
  25. 25.
    Stephens PJ, Greenman CD, Fu B et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40PubMedCrossRefGoogle Scholar
  26. 26.
    Taub R, Kirsch I, Morton C et al (1982) Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A 79:7837–7841PubMedCrossRefGoogle Scholar
  27. 27.
    Wagner LM, Smolarek TA, Sumegi J et al (2012) Assessment of minimal residual disease in ewing sarcoma. Sarcoma 2012:780129PubMedCrossRefGoogle Scholar
  28. 28.
    Wang L, Motoi T, Khanin R et al (2012) Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosomes Cancer 51:127–139PubMedCrossRefGoogle Scholar
  29. 29.
    Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMedCrossRefGoogle Scholar
  30. 30.
    Yang J, Yang D, Sun Y et al (2011) Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma. Cancer 117:4925–4938PubMedCrossRefGoogle Scholar
  31. 31.
    Ye Y, Pringle LM, Lau AW et al (2010) TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB. Oncogene 29:3619–3629PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Gerhard-Domagk-Institut für PathologieUniversitätsklinikum MünsterMünsterDeutschland

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