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

Amary, Maria Fernanda; Damato, Stephen; Halai, Dina; Eskandarpour, Malihe; Berisha, Fitim; Bonar, Fiona; McCarthy, S.; Fantin, Valeria R.; Straley, Kimberly; Lobo, Samira; Aston, Will; Green, Claire L; Gale, Rosemary E.; Tirabosco, Roberto; Futreal, Andrew; Campbell, Peter J.; Presneau, Nadège; Flanagan, Adrienne M.

doi:10.1038/ng.994

Cited by 386 publications

(320 citation statements)

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“…Previous studies found IDH mutations in a variety of benign and malignant musculoskeletal tumors, including osteosarcomas and giant cell tumors of bone (16,31,32). Furthermore, the mouse mesenchymal cell line C3H10T1/2 expressing the IDH2 R172K mutation can give rise to poorly differentiated sarcomas in xenograft models (17).…”

Section: Discussionmentioning

confidence: 99%

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Mutant IDH is sufficient to initiate enchondromatosis in mice

Hirata

Sato

Cairns

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

118

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Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to D-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or D-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.isocitrate dehydrogenase | cartilage tumor | hedgehog E nchondromas, one of the most common benign tumors occurring in bone, are present in more than 3% of the population (1, 2). They are composed of cells derived from chondrocytes and occur as solitary lesions or multiple lesions in enchondromatosis syndromes (Ollier disease or Maffucci syndrome-in the latter, enchondromas are associated with vascular malformations). Clinical problems caused by enchondromas include pain, fractures, and skeletal deformity. There is a potential for malignant progression to chondrosarcoma that may be greater than 50% in some cases of multiple enchondromatosis (i.e., Maffucci syndrome) (3-7). Many chondrosarcomas are thought to derive from enchondromas, and such sarcomas are termed central chondrosarcomas (3).The hedgehog (Hh) signaling pathway is constitutively active in enchondromas and chondrosarcomas (8,9). Hh is important in growth-plate chondrocyte differentiation, where it cooperates with parathyroid hormone-like hormone in a negative feedback loop to inhibit the differentiation of proliferative growth-plate chondrocytes (6,(10)(11)(12)(13)(14). Disruption of this feedback loop can result in either skeletal dysplasias with abnormal bone growth or enchondromas; 5% of enchondromas harbor mutation in parathyroid hormone-like hormone receptor (PTHR1), resulting in activation of Hh signaling (6,(10)(11)(12)(13)(14), and expression of a mutant PTHR1 or overexpression of the Hh-regulated transcription factor Gli2 under the Col2a1 promoter causes enchondroma-like cartilage lesions to develop adjacent to the growth-plate ...

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Section: Discussionmentioning

confidence: 99%

“…The majority of enchondromas and chondrosarcomas harbor somatic isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations (15)(16)(17)(18). Mutations in IDH genes are common in several other neoplasms, including glioma, glioblastoma, acute myeloid leukemia, angioimmunoblatic T-cell lymphoma, and intrahepatic cholangiocarcinomas (19)(20)(21)(22).…”

mentioning

confidence: 99%

Mutant IDH is sufficient to initiate enchondromatosis in mice

Hirata

Sato

Cairns

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

118

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“…Mutations in IDH1 and IDH2 were found in 75% of grade 2 to 3 gliomas and secondary glioblastoma, and in about 20% of AML [36][37][38][39][40][41][42][43][44][45][46][47][48]. Following the discovery in glioma and AML, IDH1 and IDH2 mutations were also found in several other human tumors, including cartilaginous tumors (75%) [49][50][51], intrahepatic cholangiocarcinoma (10%) [52,53], thyroid carcinomas (16%) [54,55], and less frequently in prostate cancer, acute B-lymphoblastic leukemia, paragangliomas, colorectal carcinoma, and melanoma [52,56,57]. Thus, IDH1 and IDH2 represent the most frequently mutated metabolic genes in human cancer ( Table 1).…”

Section: Idh1 and Idh2 Are Most Frequently Mutated Metabolic Genes Inmentioning

confidence: 99%

Metabolic alteration in tumorigenesis

Yang

Guan

2013

Sci. China Life Sci.

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Altered metabolism in cancer was first discovered by Otto Warburg early last century. Although the Warburg Effect has been widely used in tumor detection, relatively little progress had been made in mechanistic understanding of cancer metabolism in the subsequent eight decades. Genetic studies have recently identified mutations in human cancer targeting multiple enzymes involved in intermediate metabolism. One emerging mechanism common to these mutant enzymes is the accumulation of a metabolite that alters the epigenetic control. Otto Warburg [1,2] first discovered that cancer cells displayed enhanced glucose uptake and aerobic glycolysis, a phenomenon often referred as the Warburg Effect nowadays. Although the mechanism underlying the Warburg Effect is still not fully understood, increased uptake of glucose provides the basis to exploit its clinical application by 18 F-deoxyglucose positron emission tomography (PET) for tumor detection [3,4]. Decades after the Warburg Effect was discovered, the mechanistic insights of how metabolic alterations contribute to tumorigenesis are just emerging. Recent studies have revealed that eight metabolic genes, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, IDH1 and IDH2, encoding for subunits of four different metabolic enzymes, fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), were mutated in a number of human cancers [5]. These findings provide compelling genetic evidence supporting the notion that altered metabolism contributes to, as opposed to the consequence of, tumorigenesis. Here, we first briefly discuss how metabolism is reprogrammed to support cancer cell proliferation. We then focus on one emerging mechanism that is common to the mutations targeting all four metabolic enzymes in accumulating a metabolite to alter the epigenetic modifications in human cancer.

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“…Moreover, elevated 2-HG levels in the brain result in increased reactive oxygen species (ROS) concentrations, potentially contributing to an increased risk of cancer (Kolker et al 2002). IDH1/2 mutations occur in some gliomas ), cartilaginous tumors (Amary et al 2011;Pansuriya et al 2011), and in acute myeloid leukemias (Ward et al 2010). In astrocytomas, oligodendrogliomas, oligoastrocytomas, and secondary glioblastomas, IDH1/2 mutations have been identified as early and frequent genetic alterations (50-93%).…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Multi-Specific Monoclonal Antibody MsMab-1 Recognizing Both IDH1 and IDH2 Mutations

Kaneko

Ogasawara

Kato

2013

Tohoku J. Exp. Med.

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Mutations of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) have been reported in gliomas, cartilaginous tumors, and acute myeloid leukemias. IDH mutations are specific to a single codon in the conserved and functionally important arginine 132 residue (R132) of IDH1 or arginine 172 residue (R172) of IDH2 in gliomas. Although IDH1 and IDH2 catalyze the oxidative carboxylation of isocitrate to α-ketoglutarate in cytosol and mitochondria, respectively, mutated IDH1/2 proteins can possess the ability to change α-ketoglutarate to an oncometabolite R(−)-2-hydroxyglutarate. We have established several monoclonal antibodies (mAbs) specific for IDH1/2 mutations. However, no multi-specific mAb against IDH1/2 mutations has been reported. For this study, we immunized mice with an IDH1-R132G peptide of 19 amino acids (GGVKPIIIGGHAYGDQYRA), and established a novel mAb MsMab-1 that recognizes IDH1-R132G, but not wild type IDH1 in enzyme-linked immunosorbent assay (ELISA). It is particularly interesting that MsMab-1 recognizes all IDH1 mutants (R132H, R132C, R132S, R132G, R132L) in ELISA. Western blot analysis also revealed that MsMab-1 reacted with recombinant proteins of IDH1-R132H, IDH1-R132S, and IDH1-R132G, but not with wild type IDH1 and other IDH1 mutations, indicating that MsMab-1 is a multi-specific anti-mutated IDH1 mAb. Unexpectedly, MsMab-1 recognizes IDH2-R172M protein, despite that the IDH1-R132G peptide shows only 73.7% identity with the equivalent portion of IDH2-R172M (GGTKPITIGMHAHGDQYKA). Moreover, MsMab-1 stained the IDH1-R132S or IDH1-R132G-expressing glioma cells in immunohistochemistry. This report is the first to establish a multi-specific anti-mutated IDH1/2 mAb, that is expected to be useful for immunohistochemical determination of IDH1/2 mutation-bearing tumors.

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

Cited by 386 publications

References 10 publications

Mutant IDH is sufficient to initiate enchondromatosis in mice

Mutant IDH is sufficient to initiate enchondromatosis in mice

Metabolic alteration in tumorigenesis

Establishment of a Multi-Specific Monoclonal Antibody MsMab-1 Recognizing Both IDH1 and IDH2 Mutations

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