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

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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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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).

Author information

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.

Correspondence to Judith V M G Bovée.

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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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