Abstract

Ollier disease and Maffucci syndrome are characterized by multiple central cartilaginous tumors that are accompanied by soft tissue hemangiomas in Maffucci syndrome. We show that in 37 of 40 individuals with these syndromes, at least one tumor has a mutation in isocitrate dehydrogenase 1 (IDH1) or in IDH2, 65% of which result in a R132C substitution in the protein. In 18 of 19 individuals with more than one tumor analyzed, all tumors from a given individual shared the same IDH1 mutation affecting Arg132. In 2 of 12 subjects, a low level of mutated DNA was identified in non-neoplastic tissue. The levels of the metabolite 2HG were measured in a series of central cartilaginous and vascular tumors, including samples from syndromic and nonsyndromic subjects, and these levels correlated strongly with the presence of IDH1 mutations. The findings are compatible with a model in which IDH1 or IDH2 mutations represent early post-zygotic occurrences in individuals with these syndromes.

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References

  1. 1.

    Cartilaginous lesions of bone. J. Orthop. Sci. 6, 457–472 (2001).

  2. 2.

    et al. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat. Genet. 30, 306–310 (2002).

  3. 3.

    , & Enchondromatosis: insights on the different subtypes. Int. J. Clin. Exp. Pathol. 3, 557–569 (2010).

  4. 4.

    , & IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 16, 387–397 (2010).

  5. 5.

    et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

  6. 6.

    et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

  7. 7.

    et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

  8. 8.

    et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334–343 (2011).

  9. 9.

    et al. Genome-wide analysis of Ollier disease: is it all in the genes? Orphanet J. Rare Dis. 6, 2 (2011).

  10. 10.

    et al. Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma. PLoS ONE 6, e19868 (2011).

  11. 11.

    et al. Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens. J. Neuropathol. Exp. Neurol. 70, 715–723 (2011).

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Acknowledgements

We are grateful to the individuals who participated in the research and to the clinicians and support staff in the London Sarcoma Service involved in their care. The research was funded by Skeletal Cancer Action Trust (SCAT) UK, The Bone Cancer Research Trust UK and The Wellcome Trust (WT077012). This research was part of the Royal National Othopaedic Hospital Musculoskeletal Research Programme and Biobank and the University College London Hospital and University College London Comprehensive Biomedical Research Programme.

Author information

Author notes

    • Stephen Damato
    •  & Dina Halai

    These authors contributed equally to this work.

Affiliations

  1. Histopathology Unit, Royal National Orthopaedic Hospital National Health Service Trust, Stanmore, UK.

    • M Fernanda Amary
    • , Stephen Damato
    • , Dina Halai
    • , Fitim Berisha
    • , Samira Lobo
    • , Roberto Tirabosco
    •  & Adrienne M Flanagan
  2. Sarcoma Genetics, University College London Cancer Institute, London, UK.

    • Malihe Eskandarpour
    • , Nadège Presneau
    •  & Adrienne M Flanagan
  3. Douglass Hanly Moir Pathology, Sydney, Australia.

    • Fiona Bonar
  4. School of Medicine, The University of Sydney, Sydney, Australia.

    • Stan McCarthy
  5. Agios Pharmaceuticals, Cambridge, Massachusetts, USA.

    • Valeria R Fantin
    •  & Kimberly S Straley
  6. Bone Tumour Unit, Royal National Orthopaedic Hospital National Health Service Trust, Stanmore, UK.

    • Will Aston
  7. Experimental Therapeutics, University College London Cancer Institute, London, UK.

    • Claire L Green
    •  & Rosemary E Gale
  8. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Andrew Futreal
    •  & Peter Campbell

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Contributions

A.M.F., M.F.A. and A.F. conceived of the project. A.M.F., M.F.A., A.F., D.H. and N.P. planned the experiments. D.H., M.E., N.P., F. Berisha, S.L., C.L.G. and R.E.G. performed the experiments. F. Bonar, R.T., S.M., A.M.F., M.F.A. and W.A. reviewed the histopathology and selected and provided the samples. V.R.F. and K.S.S. performed 2HG measurements. A.M.F., M.F.A. and S.D. wrote the manuscript. P.C. performed the statistical analysis. All authors reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Adrienne M Flanagan.

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DOI

https://doi.org/10.1038/ng.994

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