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Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Nature Genetics volume 43, pages 1256–1261 (2011)Cite this article

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Abstract

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.

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Figure 1: Frequency of IDH1 and IDH2 alterations.
Figure 2: Immunostaining for mutant IDH1 R132H protein.
Figure 3: CpG island methylator phenotype in enchondromas with IDH1 mutations.

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Gene Expression Omnibus

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Acknowledgements

We are grateful to all of the participants and their families for taking part in this study. We would like to thank S. Romeo and C.M.A. Reijnders for providing DNA from cartilage tumors. We are grateful to A.B. Mohseny for help with statistics, to D. van der Geest and T. Krenács for constructing TMAs and to P. Wijers-Koster, D. de Jong, B. van den Akker, R. Duim, M. Winter, I.H. Briaire-de Bruijn and M.E. Bowen for expert technical assistance. C.J.F. Waaijer, P.C.W. Hogendoorn and C.E. de Andrea are acknowledged for fruitful discussion. We would like to acknowledge F. Bertoni, E.L. Staals and P. Bacchini for kindly providing peripheral dedifferentiated chondrosarcomas and vascular tumors, T. Kalinski for the C3842 cell line, M. Namba for the OUMS27 cell line, T. Ariizumi for the NDCS1 cell line and A. Llombart Bosch for the CH2879 cell line. J. Mulliken, J. Upton and S. Fishman kindly provided spindle cell hemangiomas. S.H.M. Verdegaal, A.H.M. Taminiau and M.A.J. van de Sande are acknowledged for contributing patient data. We are thankful to S. Boeuf, R. Forsyth and P.P. Mainil-Varlet for providing single Ollier disease cases and to W. Wutys for providing a single metachondromatosis case. The continuous support of the Netherlands Committee on Bone Tumors is highly acknowledged. The study was funded by The Netherlands Organization for Scientific Research (917-76-315 to J.V.M.G.B. and T.C.P.), the Liddy Shriver Sarcoma Initiative (to J.V.M.G.B. and J.O.), the Interuniversity Attraction Poles initiated by the Belgian Federal Science Policy, network 6/05, the US National Institutes of Health (AR048564) and the FNRS–Fonds de la Recherche Scientifique (all to M.V.) and the Manton Center for Orphan Disease Research at Children's Hospital Boston (94824-01 to K.K.). The study was performed within the EuroBoNeT, a European Commission-granted Network of Excellence for studying the pathology and genetics of bone tumors (018814).

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Authors and Affiliations

  1. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

    Twinkal C Pansuriya, Ronald van Eijk, Maayke A J H van Ruler, Marieke L Kuijjer, Jan Oosting, Anne-Marie Cleton-Jansen, Jolieke G van Oosterwijk, Sofie L J Verbeke, Daniëlle Meijer, Tom van Wezel & Judith V M G Bovée

  2. Institute for Maternal and Child Health, Instituto di Ricovero e Cura a Carattere Scientifico, Burlo Garofolo, University of Trieste, Trieste, Italy

    Pio d'Adamo

  3. Department of Pathology, University Hospital Antwerp, Antwerp, Belgium

    Sofie L J Verbeke

  4. Department of Clinical Genetics, Lund University Hospital, Lund, Sweden

    Karolin H Nord

  5. Department of Medical Genetics, Rizzoli Orthopedic Institute, Bologna, Italy

    Luca Sangiorgi

  6. Istanbul University Medical School, Istanbul, Turkey

    Berkin Toker

  7. Institute of Pathology, Medical University, Graz, Austria

    Bernadette Liegl-Atzwanger

  8. Department of Orthopaedic Surgery and Traumatology, University Clinic of Navarra, Pamplona, Spain

    Mikel San-Julian

  9. Department of Pathology, University of Leuven, Leuven, Belgium

    Raf Sciot, Laurence M Boon & Miikka Vikkula

  10. de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    Nisha Limaye

  11. Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital, Birmingham, UK

    Lars-Gunnar Kindblom

  12. Department of Pathology, University of Copenhagen, Copenhagen, Denmark

    Soeren Daugaard

  13. Laboratory of Pathology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

    Catherine Godfraind

  14. Division of Plastic Surgery, Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

    Laurence M Boon

  15. Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, Brussels, Belgium

    Miikka Vikkula

  16. Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA

    Kyle C Kurek

  17. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

    Karoly Szuhai

  18. Department of Neurology, Erasmus University Medical Center, Erasmus University, Rotterdam, The Netherlands

    Pim J French

Authors
  1. Twinkal C Pansuriya
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Contributions

The study was designed, written and reviewed by T.C.P. and J.V.M.G.B. Mutation analysis was designed and performed by T.C.P., M.A.J.H.v.R., J.V.M.G.B., K.S., T.v.W. and R.v.E. Immunohistochemistry was conducted and evaluated by T.C.P., M.A.J.H.v.R. and J.V.M.G.B. T.C.P., S.L.J.V., J.G.v.O. and D.M. contributed tissue microarrays. Expression profiling was designed and performed by A.-M.C.-J., T.C.P., J.V.M.G.B. and J.O. and analyzed by J.O. and M.L.K. Methylation profiling was designed by A.-M.C.-J., J.V.M.G.B. and L.S., performed by P.d.A., and the results analyzed by P.d.A. and P.J.F. K.H.N., S.D., L.S., B.T., B.L.-A., M.S.-J., R.S., N.L., L.-G.K., C.G., M.V., L.M.B. and K.C.K. each contributed frozen or paraffin-embedded tissues for multiple subjects with Ollier disease or Maffucci syndrome and acquired data for these individuals. The manuscript was approved by all authors.

Corresponding author

Correspondence to Judith V M G Bovée.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 and Supplementary Tables 1, 2 and 4–6 (PDF 21614 kb)

Supplementary Table 3

Differentially methylated sites in enchondromas with and without IDH1 mutation at Sanger sequencing (XLS 391 kb)

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Pansuriya, T., van Eijk, R., d'Adamo, P. et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43, 1256–1261 (2011). https://doi.org/10.1038/ng.1004

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