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Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2

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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Figure 1: Clinical features of individuals with Ollier disease or Maffucci syndrome who harbor an IDH1 mutation encoding an R132C substitution.
Figure 2: Comparison of 2HG levels in tumors with wild-type (WT) or mutated IDH1 and IDH2.

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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.

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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.

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Correspondence to Adrienne M Flanagan.

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The authors declare no competing financial interests.

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Amary, M., Damato, S., Halai, D. et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 43, 1262–1265 (2011). https://doi.org/10.1038/ng.994

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