Cancer-associated IDH mutations: biomarker and therapeutic opportunities

Yen, Katharine; Bittinger, Mark; Su, Shinsan M.; Fantin, Valeria R.

doi:10.1038/onc.2010.444

Cited by 272 publications

(221 citation statements)

References 62 publications

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“…Our data also confirm that IDH1 mutations occur frequently whereas IDH2 mutations rarely. As previously reported (27,28), these two mutations are mutually exclusive (100% of cases in our series), suggesting that they are involved in similar tumorigenesis pathways.…”

Section: Discussionsupporting

confidence: 86%

IDH mutations occur frequently in Chinese glioma patients and predict longer survival but not response to concomitant chemoradiotherapy in anaplastic gliomas

et al. 2011

Oncol Rep

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Abstract. Mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) appear to occur frequently and selectively in gliomas. Our aim was to assess whether IDH mutations are common in Chinese glioma patients and whether the mutations predict good response to concomitant chemoradiotherapy. In this study IDH1 and IDH2 mutations were detected in a series of 203 gliomas. IDH1 mutations were present in 75 of the 203 cases (36.9%) while IDH2 mutations in 5 of the 203 cases (2.5%). No tumor was mutated in both IDH1 and IDH2. IDH1/2 mutations were associated with prolonged overall survival in the whole series of patients exclusive of pilocytic astrocytoma (P<0.001), WHO grade Ⅱ patients who received no adjuvant therapy after surgery (P= 0.014) and WHO grade Ⅲ patients who received concomitant chemoradiotherapy (standard schedule) after surgery (P=0.033). Furthermore, there was no correlation between IDH1/2 mutations and reponse to concomitant chemoradiotherapy in anaplastic gliomas. Our results suggest that IDH1 mutations also occur freuqently in Chinese glioma patients but the frequency of IDH1 mutations is below the findings reported by North American and European groups. Furthermore, we confirm the prognostic significance of IDH1/2 mutations in gliomas, but the mutations cannot predict a favorable response to concomitant chemoradiotherapy in anaplastic gliomas. IntroductionGliomas are the most frequent and lethal brain tumors and display a wide diversity with location, morphology, genetic status and response to therapy. These tumors have been classified as grade I to grade IV based on histopathological and clinical criteria established by the World Health Organization (WHO) (1). Despite intensive therapies, including surgery, radiotherapy (RT) and chemotherapy (CT), the outcome of glioma patients remain depressing (2,3). Especially, glioblastoma multiforme (GBM), the most prevalent form of brain tumors, has one of the worst prognosis among all types of gliomas with a median progression-free survival (PFS) of 6.9 months and a median overall survival (OS) of 14.6 months through surgery plus standard concomitant chemoradiotherapy (CCRT) (2,4).A combined understanding of the genetic basis and pathology of gliomas provides insight into biologically based tumor classification and identifies molecular prognostic biomarkers. In turn, this information is the route by which the most effective therapy can be focused (5). The latest breakthrough came in 2008, when the gene encoding isocitrate dehydrogenase 1 (IDH1) was initially found to be mutated in approximately 12% of GBM (6) followed by the observation that it was mutated in the majority of WHO grade II and III gliomas (7-11). IDH1 (encoded by IDH1 gene on chromosomal 2q33.3 and located in the cytoplasm and peroxisomes) or its mitochondrial counterpart IDH2, is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate thereby leading to NADPH (Nicotinamide Adenine Dinucleotide Phosphate) production (12). In the vast majority of the c...

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Section: Discussionsupporting

confidence: 86%

IDH mutations occur frequently in Chinese glioma patients and predict longer survival but not response to concomitant chemoradiotherapy in anaplastic gliomas

et al. 2011

Oncol Rep

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“…Somatic mutations were found to be present in IDH1 and IDH2 in 88% of individuals with secondary glioblastomas, 68% of those with grade II glioma (lower grade diffuse astrocytomas), 78% of those with grade III anaplastic astrocytomas, and 69% of those with grade III anaplastic oligodendrogliomas (Dang, Jin et al 2010;Dang, White et al 2010) as well as 31% of patients with myeloproliferative neoplasm (Green and Beer 2010) and 10% of those with acute myeloid leukemia (AML) (Dang, Jin et al 2010;Yen, Bittinger et al 2010). Mutations in IDH were first reported to be activating mutations, but subsequent studies of mutations at arginine R132 (in IDH1) and at R140 or R172 (in IDH2) in the enzyme showed a gain of new function and the ability to convert alpha-ketoglutarate to 2-hydroxyglutarate (Dang, White et al 2009).…”

Section: Mutations At Idh1 and Idh2mentioning

confidence: 99%

“…Mutations in these metabolic enzymes uncover novel avenues for the development of anticancer therapeutics, but specific inhibitors are needed for the mutated forms R132, R140, or R172. It is not clear what the role of this mutation is in cancer and whether it is crucial for tumorigenesis, although the 2-hydroxyglutarate metabolite is a biomarker that can be measured in whole blood and used to select targeted therapy (Yen, Bittinger et al 2010). …”

Section: Mutations At Idh1 and Idh2mentioning

confidence: 99%

Activating Mutations and Targeted Therapy in Cancer

Tuna¹,

Amos²

2012

Mutations in Human Genetic Disease

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“…IDH mutations have been identified in breast, colon cancers (Yen et al, 2010) and glioblastomas (Dang et al, 2010;Prensner and Chinnaiyan, 2011), and when IDH mutations occur in AML they are viewed as poor prognostic indicators and are thought to drive disease progression (Prensner and Chinnaiyan, 2011).…”

Section: Gene Mutationsmentioning

confidence: 99%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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Access to the full text of the published version may require a subscription. and ideas for this work, and who supported and believed in me throughout -I am grateful to have had the opportunity to learn from the best. I must also give a huge thank you to Kate Cotter, who made me feel at home from day one, and who has continued to be a tireless source of energy and assistance. RightsI was fortunate to interact with a vibrant, dynamic group in the Cotter Lab and I owe a huge thanks to every single member, past-Claire, Ruth, Carolyn, Chris, Ashley, To all the friends that I have made in U.C.C. and beyond during this process, as well as those friends lucky enough not to be involved but who still got to listen to all that whingeing-thank you! Lastly, I am most indebted to those closest to me. My mam -who is always ready to listen, comfort and reassure, and as a result probably knows more than she ever wanted to about cells and reactive oxygen species! My dad, a real scientist, who never stops teaching and never stops learning, and is still the person I turn to with my "homework" questions! I am so grateful to you both for your wisdom, encouragement and patience; truly I could not have achieved this without you. ToSinead and Dara, for all the much needed distractions and laughs, and for even being interested! And to John, for being there throughout, for the joy and the inspiration. To everyone still waiting for good news or the right medicine 'Happy is he who gets to know the reasons for things.' -Virgil DeclarationThis thesis has not been submitted in whole or in part to this or any other university for any degree and is, unless otherwise stated, the original work of the author. pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to iii NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study.The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalli...

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Cancer-associated IDH mutations: biomarker and therapeutic opportunities

Cited by 272 publications

References 62 publications

IDH mutations occur frequently in Chinese glioma patients and predict longer survival but not response to concomitant chemoradiotherapy in anaplastic gliomas

IDH mutations occur frequently in Chinese glioma patients and predict longer survival but not response to concomitant chemoradiotherapy in anaplastic gliomas

Activating Mutations and Targeted Therapy in Cancer

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

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