Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation

Oncogene volume 29, pages 3827–3834 (2010)Cite this article

Subjects

Abstract

Osteochondroma, the most common benign bone tumor, may occur as a sporadic lesion or as multiple neoplasms in the context of multiple osteochondromas syndrome. The most severe complication is malignant transformation into peripheral secondary chondrosarcoma. Although both benign conditions have been linked to defects in EXT1 or EXT2 genes, contradictory reports are present in the literature regarding the requirement of their biallelic inactivation for osteochondroma development. A major limitation of these studies is represented by the small number of samples available for the screening. Taking advantage of a large series of tissues, our aim was to contribute to the definition of a genetic model for osteochondromas onset and transformation. EXT genes point mutations and big deletions were analyzed in 64 tissue samples. A double hit was found in 5 out of 35 hereditary cases, 6 out of 16 chondrosarcomas and 2 recurrences; none of the 11 sporadic osteochondromas showed two somatic mutations. Our results clearly indicate that, in most cases, biallelic inactivation of EXT genes does not account for osteochondromas formation; this mechanism should be regarded as a common feature for hereditary osteochondromas transformation and as an event that occurs later in tumor progression of solitary cases. These findings suggest that mechanisms alternative to EXT genetic alteration likely have a role in osteochondromas pathogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs MB et al. (2001). Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Cell Motil Cytoskeleton 48: 149–162.

    Article  CAS  PubMed  Google Scholar 

  • Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ et al. (1999a). Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Genes Chrom Cancer 26: 237–246.

    Article  PubMed  Google Scholar 

  • Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E et al. (1999b). EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet 65: 689–698.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR . (1998). Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11–12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer 82: 1657–1663.

    Article  CAS  PubMed  Google Scholar 

  • Cheung PK, McCormick C, Crawford BE, Esko JD, Tufaro F, Duncan G . (2001). Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity. Am J Hum Genet 69: 55–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Essadki B, Moujtahid M, Lamine A, Fikry T, Essadki O, Zryouil B . (2000). Solitary osteochondroma of the limbs. Clinical review of 76 cases and pathogenic hypothesis. Acta Orthop Belg 66: 146–153.

    CAS  PubMed  Google Scholar 

  • Farach-Carson MC, Hecht JT, Carson DD . (2005). Heparan sulfate proteoglycans: key players in cartilage biology. Crit Rev Eukaryot Gene Expr 15: 29–48.

    Article  CAS  PubMed  Google Scholar 

  • Hall CR, Cole WG, Haynes R, Hecht JT . (2002). Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis. Am J Med Genet 112: 1–5.

    Article  PubMed  Google Scholar 

  • Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, van Dekken H et al. (2007). The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. J Natl Cancer Inst 99: 396–406.

    Article  CAS  PubMed  Google Scholar 

  • Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M . (1995). Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXT-linked markers on chromosomes II and 8. Am J Hum Genet 56: 1125–1131.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hennekam RC . (1991). Hereditary multiple exostoses. J Med Genet 28: 262–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huvos AG . (1991). Bone Tumors: Diagnosis, Treatment, and Prognosis, 2nd edn. WB Saunders: Philadelphia.

  • Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG et al. (2009). Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat 30: 1620–1627.

    Article  CAS  PubMed  Google Scholar 

  • Knudson Jr AG . (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823.

    Article  PubMed  Google Scholar 

  • Lonie L, Porter DE, Fraser M, Cole T, Wise C, Yates L et al. (2006). Determination of the mutation spectrum of the EXT1/EXT2 genes in British Caucasian patients with multiple osteochondromas, and exclusion of six candidate genes in EXT negative cases. Hum Mutat 27: 1160.

    Article  PubMed  Google Scholar 

  • Ludecke H-J, Ahn J, Lin X, Hill A, Wagner M J, Schomburg L et al. (1997). Genomic organization and promoter structure of the human EXT1 gene. Genomics 40: 351–354.

    Article  CAS  PubMed  Google Scholar 

  • McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP et al. (1998). The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nature Genet 19: 158–161.

    Article  CAS  PubMed  Google Scholar 

  • McCormick C, Duncan G, Goutsos KT, Tufaro F . (2000). The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 97: 668–673.

    Article  CAS  PubMed  Google Scholar 

  • Mertens F, Rydholm A, Kreicbergs A, Willen H, Jonsson K, Heim S et al. (1994). Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Genes Chromosom Cancer 9: 8–12.

    Article  CAS  PubMed  Google Scholar 

  • Pedrini E, De Luca A, Valente EM, Maini V, Capponcelli S, Mordenti M et al. (2005). Novel EXT1 and EXT2 mutations identified by DHPLC in Italian patients with multiple osteochondromas. Hum Mutat 26: 280.

    Article  PubMed  Google Scholar 

  • Porter DE, Simpson AH . (1999). The neoplastic pathogenesis of solitary and multiple osteochondromas. J Pathol 188: 119–125.

    Article  CAS  PubMed  Google Scholar 

  • Raskind WH, Conrad EU, Chansky H, Matsushita M . (1995). Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Am J Hum Genet 56: 1132–1139.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rohlin A, Wernersson J, Engwall Y, Wiklund L, Björk J, Nordling M . (2009). Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques. Hum Mutat 30: 1012–1020.

    Article  CAS  PubMed  Google Scholar 

  • Schmale GA, Conrad III EU, Raskind WH . (1994). The natural history of hereditary multiple exostoses. J Bone Joint Surg Am 76: 986–992.

    Article  CAS  PubMed  Google Scholar 

  • Solomon L . (1964). Hereditary multiple exostosis. Am J Hum Genet 16: 351–363.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Springfield DS, Gebhardt MC, McGuire MH . (1996). Chondrosarcoma: a review. Instr Course Lect 45: 417–424.

    CAS  PubMed  Google Scholar 

  • Traeger-Synodinos J . (2006). Real-time PCR for prenatal and preimplantation genetic diagnosis of monogenic diseases. Mol Aspects Med 27: 176–191.

    Article  CAS  PubMed  Google Scholar 

  • Trebicz-Geffen M, Robinson D, Evron Z, Glaser T, Fridkin M, Kollander Y et al. (2008). The molecular and cellular basis of exostosis formation in hereditary multiple exostoses. Int J Exp Pathol 89: 321–331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wicklund CL, Pauli RM, Johnston D, Hecht JT . (1995). Natural history study of hereditary multiple exostoses. Am J Med Genet 55: 43–46.

    Article  CAS  PubMed  Google Scholar 

  • Wu Y-Q, Heutink P, de Vries BBA, Sandkuijl LA, van den Ouweland AM, Niermeijer MF et al. (1994). Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Hum Mol Genet 3: 167–171.

    Article  CAS  PubMed  Google Scholar 

  • Wuyts W, Ramlakhan S, Van Hul W, Hecht JT, van den Ouweland AM, Raskind WH et al. (1995). Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11. Am J Hum Genet 57: 382–387.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F et al. (1998). Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet 62: 346–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wuyts W, Van Hul W . (2000). Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat 15: 220–227.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the European Project EuroBoNeT.

Author information

Author notes

  1. M Zuntini and E Pedrini: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics and Skeletal Rare Diseases, Rizzoli Orthopaedic Institute, Bologna, Italy

    M Zuntini, E Pedrini, A Parra, F Sgariglia, F V Gentile, M Pandolfi & L Sangiorgi

  2. Department of Anatomical Pathology and Histology, Rizzoli Orthopaedic Institute, Bologna, Italy

    M Alberghini

Authors
  1. M Zuntini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Pedrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Parra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Sgariglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F V Gentile
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Pandolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Alberghini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L Sangiorgi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Sangiorgi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zuntini, M., Pedrini, E., Parra, A. et al. Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation. Oncogene 29, 3827–3834 (2010). https://doi.org/10.1038/onc.2010.135

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.135

Keywords

This article is cited by

Search

Advanced search

Quick links