title: Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome.
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.
authors: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors: Twinkal C
authors: TC
authors: Pansuriya
authors: Ronald
authors: R
authors: van Eijk
authors: Pio
authors: P
authors: d'Adamo
authors: Maayke A J H
authors: MA
authors: van Ruler
authors: Marieke L
authors: ML
authors: Kuijjer
authors: Jan
authors: J
authors: Oosting
authors: Anne-Marie
authors: AM
authors: Cleton-Jansen
authors: Jolieke G
authors: JG
authors: van Oosterwijk
authors: Sofie L J
authors: SL
authors: Verbeke
authors: Daniëlle
authors: D
authors: Meijer
authors: Tom
authors: T
authors: van Wezel
authors: Karolin H
authors: KH
authors: Nord
authors: Luca
authors: L
authors: Sangiorgi
authors: Berkin
authors: B
authors: Toker
authors: Bernadette
authors: B
authors: Liegl-Atzwanger
authors: Mikel
authors: M
authors: San-Julian
authors: Raf
authors: R
authors: Sciot
authors: Nisha
authors: N
authors: Limaye
authors: Lars-Gunnar
authors: LG
authors: Kindblom
authors: Soeren
authors: S
authors: Daugaard
authors: Catherine
authors: C
authors: Godfraind
authors: Laurence M
authors: LM
authors: Boon
authors: Miikka
authors: M
authors: Vikkula
authors: Kyle C
authors: KC
authors: Kurek
authors: Karoly
authors: K
authors: Szuhai
authors: Pim J
authors: PJ
authors: French
authors: Judith V M G
authors: JV
authors: Bovée
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004687:Enchondromatosis / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human