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

• Published in: Nature genetics Vol. 43; no. 12; pp. 1256 - 1261
• Main Authors: Pansuriya, Twinkal C, van Eijk, Ronald, d'Adamo, Pio, van Ruler, Maayke A J H, Kuijjer, Marieke L, Oosting, Jan, Cleton-Jansen, Anne-Marie, van Oosterwijk, Jolieke G, Verbeke, Sofie L J, Meijer, Daniëlle, van Wezel, Tom, Nord, Karolin H, Sangiorgi, Luca, Toker, Berkin, Liegl-Atzwanger, Bernadette, San-Julian, Mikel, Sciot, Raf, Limaye, Nisha, Kindblom, Lars-Gunnar, Daugaard, Soeren, Godfraind, Catherine, Boon, Laurence M, Vikkula, Miikka, Kurek, Kyle C, Szuhai, Karoly, French, Pim J, Bovée, Judith V M G
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2011; Nature Publishing Group
• Subjects: 631/208/2489/144/68; 692/699/67/1344; Adult; Agriculture; Animal Genetics and Genomics; Basic Medicine; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; Case-Control Studies; Cell Line, Tumor; Complications and side effects; Deoxyribonucleic acid; Diagnosis; Disease; Diseases of the osteoarticular system; DNA; DNA Methylation; Enchondromatosis - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation; Gene Function; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Hemangioma; Human Genetics; Humans; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Lesions; letter; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical and Health Sciences; Medical Genetics; Medical Genetics and Genomics (including Gene Therapy); Medical sciences; Medicin och hälsovetenskap; Medicinsk genetik; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Mosaicism; Musculoskeletal diseases; Mutation; Mutation, Missense; Physiological aspects; Risk factors; Sequence Analysis, DNA; Transcription, Genetic; Tumors; Tumors of striated muscle and skeleton; Young Adult; Belgium; Italy; Spain; Skin disease; Diseases of the osteoarticular system; Cardiovascular disease; Enchondroma; Congenital disease; Vascular disease; Osteoarticular system; Angioma; Chondroma; Syndrome de Maffucci; Benign neoplasm; Mutation; Bone; Osteochondrodysplasia
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.1004

Judith Bovée and colleagues report the identification of somatic mosaic mutations in IDH1 and IDH2 in tumors from individuals with Ollier disease and Maffucci syndrome, which are non-hereditary skeletal disorders characterized by multiple enchondromas. 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.