<i>IDH1</i> mutations are not found in cartilaginous tumours other than central and periosteal chondrosarcomas and enchondromas

Damato, Stephen; Alorjani, Mohammed; Bonar, Fiona; McCarthy, Stanley W.; Cannon, Stephen R.; O’Donnell, Paul; Tirabosco, Roberto; Amary, Maria Fernanda; Flanagan, Adrienne M.

doi:10.1111/j.1365-2559.2011.04010.x

Cited by 63 publications

(38 citation statements)

References 6 publications

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“…In the present study, neither conventional RT-PCR nor qPCR demonstrated expression of HMGA2 in the examined periosteal chondromas. The mutation analysis of IDH1 and IDH2 revealed that the tumors carried heterozygous IDH1 mutations at R132, which are in accordance with previous observations that a majority of periosteal chondromas carry heterozygous mutations at R132 of IDH1 (5,6). From the results of the present study it can be hypothesized that the rearrangements and expression of HMGA2 are mutually exclusive with IDH1 and IDH2 mutations in periosteal chondromas.…”

Section: Discussionsupporting

confidence: 80%

“…Of the eight periosteal chondromas previously analyzed for the presence of mutations in IDH1, mutations were observed in six: Four possessed IDH1R132C (CGT>TGT) and two possessed R132S (CGT>AGT) (4,5). Viewing the present and previously published data in concert (5,6), mutations in codon 12 of IDH1 have been present in the majority (83%, 10/12) of examined periosteal chondromas. Of those mutations in the IDH1, R132C comprises 60% (6/10), whereas R132L and R132S are observed in 20% (2 cases each).…”

Section: Discussionsupporting

confidence: 53%

“…In other studies, IDH1 mutations were observed in 6 out of the 8 periosteal chondromas examined (5,6). The present study investigated cytogenetic and molecular genetic data in 4 cases of periosteal chondroma.…”

Section: Introductionmentioning

confidence: 99%

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Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas

et al. 2015

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Abstract. Periosteal chondroma is a benign cartilage tumor that accounts for <2% of chondromas. In the present study, four cases of periosteal chondromas were cytogenetically investigated and studied for the expression of high-mobility group AT-hook 2 (HMGA2), mutations in codons 132 of isocitrate dehydrogenase (IDH)1 and 172 of IDH2; mutations -C228T and -C250T in the promoter region of telomerase reverse transcriptase (TERT); and for methylation in the promoter regions of O-6-methylguanine-DNA methyltransferase (MGMT) and cellular retinol binding protein 1 (CRBP1). Chromosome aberrations of 12q13-15 were found in two out of the four tumors, while two had a normal karyotype. Two periosteal chondromas carried the mutation IDH1R132C (CGT>TGT), and two carried the mutation IDH1R132L (CGT>CTT). However, none of the four tumors had methylated MGMT and CRBP1 promoters or mutations at codon 172 of IDH2. In addition, -C228T and -C250T mutations were not present in the promoter region of TERT, nor was HMGA2 demonstrated to be expressed. The present study indicated that in periosteal chondromas, the involvement of 12q13-15 in structural rearrangements may be recurrent but that HMGA2 is not expressed. Additionally, the periosteal chondromas investigated in the study carried a heterozygous IDH1R132 mutation, the MGMT and CRBP1 promoters were not methylated, and -C228T and -C250T mutations in the promoter region of TERT were absent.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 53%

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Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas

et al. 2015

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“…96 In a related arena, the HIF signalling pathway is potentially involved in the initiation and progression of human chondrosarcomas. [97][98] Mutations that affect isocitrate dehydrogenases 1 and 2 occur in human chondrosarcomas, [97][98] and lead to depletion of the co-factor α-ketoglutarate-which, in turn, could lead to increased accumulation of HIFs through inhibition of HIF prolyl hydroxylases. 99 The HIF signalling pathway might, therefore, be altered in chrondrosarcomas, which could contribute, at least in part, to the initiation and/or progression of these malignancies.…”

Section: [H2] Metastasis To Bonementioning

confidence: 99%

Hypoxia-driven pathways in bone development, regeneration and disease

2012

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Adaptation to hypoxia is a critical cellular event both in pathological settings, such as cancer and ischemia, and in normal development and differentiation. Oxygen is thought to be not only an indispensable metabolic substrate for a variety of in vivo enzymatic reactions including mitochondrial respiration, but also a key regulatory signal in tissue development and homeostasis by controlling a specific genetic program. Hypoxiainducible transcription factors (HIFs) HIF-1 and HIF-2 are central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Genetically altered mice have identified important roles for HIF-1 and HIF-2 as well as vascular endothelial growth factor-A (VEGF)-a potent angiogenic factor and a downstream target of the HIF pathway-in the regulation of skeletal development, bone homeostasis and haematopoiesis. In this Review, we summarize the current knowledge of HIF signalling in cartilage, bone and haematopoiesis, and pay particular attention to the complex relationship between HIF and VEGF in these tissues based on data collected in animal models. The study of these models expands our understanding of the cell autonomous, paracrine and autocrine effects that mediate the homeostatic responses downstream of HIFs and VEGF. This knowledge can also be relevant for diseases like cancer and ischemia.

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“…The NADP + -dependent IDH genes IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al 2008), ;20% of acute myeloid leukaemia (AML) (Mardis et al 2009), and several additional tumors at different frequencies (Hemerly et al 2010;Murugan et al 2010;Amary et al 2011;Damato et al 2012;Oermann et al 2012). These mutations in IDH1/2 result in simultaneous loss and gain of activities in the production of a-ketoglutarate (a-KG) and 2-hydroxyglutarate (2-HG), respectively (Dang et al 2009;Yan et al 2009;Zhao et al 2009).…”

mentioning

confidence: 99%

Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors

Xiao¹,

Yang²,

Xu³

et al. 2012

Genes Dev.

915

850

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Two Krebs cycle genes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple a-ketoglutarate (a-KG)-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases. Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of a-KG to broadly inhibit the activity of a-KG-dependent dioxygenases. In addition, ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC. Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple a-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation. These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.[Keywords: FH; SDH; metabolites; a-KG-dependent dioxygenases; DNA methylation; histone methylation] Supplemental material is available for this article. Received March 7, 2012; revised version accepted May 9, 2012. Several lines of evidence, including the recent identification of mutations affecting isocitrate dehydrogenase (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), have demonstrated that mutations in certain metabolic enzymes may play a causal role in tumorigenesis. The NADP + -dependent IDH genes IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al. 2008),

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IDH1 mutations are not found in cartilaginous tumours other than central and periosteal chondrosarcomas and enchondromas

Cited by 63 publications

References 6 publications

Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas

Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas

Hypoxia-driven pathways in bone development, regeneration and disease

Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors

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