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. 2011 Nov 6;43(12):1256-61.
doi: 10.1038/ng.1004.

"VSports在线直播" Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Twinkal C Pansuriya  1 , Ronald van Eijk, Pio d'Adamo, 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, Karolin H Nord, Luca Sangiorgi, Berkin Toker, Bernadette Liegl-Atzwanger, Mikel San-Julian, Raf Sciot, Nisha Limaye, Lars-Gunnar Kindblom, Soeren Daugaard, Catherine Godfraind, Laurence M Boon, Miikka Vikkula, Kyle C Kurek, Karoly Szuhai, Pim J French, Judith V M G Bovée
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"V体育ios版" Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Twinkal C Pansuriya et al. Nat Genet. .

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 VSports手机版. .

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Figure 1
Figure 1. Frequency of IDH1 and IDH2 mutations
a) Distribution of the different R132 IDH1 and R172 IDH2 mutations among the patients with Ollier disease, Maffucci syndrome and solitary tumors. b) Frequency of somatic heterozygous IDH (IDH1 and IDH2) mutations in tumors of patients with Ollier disease and Maffucci syndrome, in comparison with different subtypes of solitary cartilaginous tumors and angiosarcomas.
Figure 2
Figure 2. Immunohistochemistry for R132H IDH1 mutant protein
a,b) Enchondroma (L1490) of patient with Ollier disease demonstrating strong cytoplasmic and nuclear staining of R132H IDH1 mutant protein. Note the mixture of wild-type and mutated cells indicating intraneoplastic mosaicism. Overall the percentage of positive tumor cells ranged from 50% to 95%. Insets show vitality of the negative cells at higher magnification. c) Grade II chondrosarcoma negative for R132H IDH1 mutant protein. d and e) Enchondromas from patients with Ollier disease demonstrating occasional positive cells in the surrounding normal bone. Some positive osteocytes (arrows) and osteoblasts (arrowheads) are seen. T: tumor tissue. (Magnification 400×)
Figure 3
Figure 3. CpG island Methylator Phenotype in enchondromas with IDH1 mutations
Heatmap depicting unsupervised clustering analysis based on the 2000 most variable CpG sites of enchondromas with IDH1 mutations (orange, n = 8) and without IDH1 mutation (gray, n=4). The level of DNA methylation (beta value) for each probe (columns) in each sample (rows) is represented by color scale as shown in the picture ranging from 0 (0% methylation, blue) to 1 (100% methylation, yellow). Asterisk indicates sample L2357 in which the R132G IDH1 mutant allele was detected in a subpopulation of cells. However, the mutation escaped detection at Sanger sequencing, and therefore the sample is labeled “wild-type”.
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References

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