Isocitrate Dehydrogenase Wild-type Glial Tumors, Including Glioblastoma

Levels of several intermediary metabolites were measured in cells grown in acetate medium in order to test the hypothesis that the glyoxylate cycle is repressed by phosphoenolpyruvate (PEP). Wild-type cells had less PEP than either isocitrate dehydrogenase – deficient cells (which had greater isocitrate lyase activity than the wild type) or isocitrate dehydrogenase – deficient, citrate synthase – deficient cells (which are poorly inducible). Thus induction of the glyoxylate cycle is more complicated than a simple function of PEP concentration. No correlation between enzyme activity and the level of oxaloacetate, pyruvate, or citrate was found either. Citrate was synthesized in citrate synthase – deficient mutants, possibly via citrate lyase.

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Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants

Biochemical Journal ◽

10.1042/bcj20180424 ◽

2018 ◽

Vol 475 (20) ◽

pp. 3221-3238 ◽

Cited By ~ 4

Author(s):

Diego Avellaneda Matteo ◽

Grace A. Wells ◽

Lucas A. Luna ◽

Adam J. Grunseth ◽

Olga Zagnitko ◽

...

Keyword(s):

Isocitrate Dehydrogenase ◽

Resistance Mutation ◽

Poor Response ◽

Fold Increase ◽

Structural Features ◽

Low Grade ◽

Wild Type ◽

Isocitrate Dehydrogenase 1 ◽

Dynamics Simulations ◽

Mutant Idh1

Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

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Huge heterogeneity in survival in a subset of adult patients with resected, wild-type isocitrate dehydrogenase status, WHO grade II astrocytomas

Journal of Neurosurgery ◽

10.3171/2017.10.jns171825 ◽

2019 ◽

Vol 130 (4) ◽

pp. 1289-1298 ◽

Cited By ~ 11

Author(s):

Gaëtan Poulen ◽

Catherine Gozé ◽

Valérie Rigau ◽

Hugues Duffau

Keyword(s):

Radiation Therapy ◽

Malignant Transformation ◽

Isocitrate Dehydrogenase ◽

Adult Patients ◽

World Health ◽

Wild Type ◽

Who Grade ◽

Grade Ii ◽

The Individual

OBJECTIVEWorld Health Organization grade II gliomas are infiltrating tumors that inexorably progress to a higher grade of malignancy. However, the time to malignant transformation is quite unpredictable at the individual patient level. A wild-type isocitrate dehydrogenase (IDH-wt) molecular profile has been reported as a poor prognostic factor, with more rapid progression and a shorter survival compared with IDH-mutant tumors. Here, the oncological outcomes of a series of adult patients with IDH-wt, diffuse, WHO grade II astrocytomas (AII) who underwent resection without early adjuvant therapy were investigated.METHODSA retrospective review of patients extracted from a prospective database who underwent resection between 2007 and 2013 for histopathologically confirmed, IDH-wt, non–1p19q codeleted AII was performed. All patients had a minimum follow-up period of 2 years. Information regarding clinical, radiographic, and surgical results and survival were collected and analyzed.RESULTSThirty-one consecutive patients (18 men and 13 women, median age 39.6 years) were included in this study. The preoperative median tumor volume was 54 cm3 (range 3.5–180 cm3). The median growth rate, measured as the velocity of diametric expansion, was 2.45 mm/year. The median residual volume after surgery was 4.2 cm3 (range 0–30 cm3) with a median volumetric extent of resection of 93.97% (8 patients had a total or supratotal resection). No patient experienced permanent neurological deficits after surgery, and all patients resumed a normal life. No immediate postoperative chemotherapy or radiation therapy was given. The median clinical follow-up duration from diagnosis was 74 months (range 27–157 months). In this follow-up period, 18 patients received delayed chemotherapy and/or radiotherapy for tumor progression. Five patients (16%) died at a median time from radiological diagnosis of 3.5 years (range 2.6–4.5 years). Survival from diagnosis was 77.27% at 5 years. None of the 21 patients with a long-term follow-up greater than 5 years have died. There were no significant differences between the clinical, radiological, or molecular characteristics of the survivors relative to the patients who died.CONCLUSIONSHuge heterogeneity in the survival data for a subset of 31 patients with resected IDH-wt AII tumors was observed. These findings suggest that IDH mutation status alone is not sufficient to predict risk of malignant transformation and survival at the individual level. Therefore, the therapeutic management of AII tumors, in particular the decision to administer early adjuvant chemotherapy and/or radiation therapy following surgery, should not solely rely on routine molecular markers.

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Anatomical location differences between mutated and wild-type isocitrate dehydrogenase 1 in low-grade gliomas

International Journal of Neuroscience ◽

10.1080/00207454.2016.1270278 ◽

2017 ◽

Vol 127 (10) ◽

pp. 873-880 ◽

Cited By ~ 9

Author(s):

Jinhua Yu ◽

Zhifeng Shi ◽

Chunhong Ji ◽

Yuxi Lian ◽

Yuanyuan Wang ◽

...

Keyword(s):

Isocitrate Dehydrogenase ◽

Anatomical Location ◽

Low Grade ◽

Wild Type ◽

Isocitrate Dehydrogenase 1 ◽

Low Grade Gliomas

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Μελέτη των μηχανικών ιδιοτήτων των γλοιωμάτων εγκεφάλου σε χειρουργικά ιστοτεμάχια

10.12681/eadd/50355 ◽

2021 ◽

Author(s):

Αβραάμ Τσιτλακίδης

Keyword(s):

Atomic Force Microscope ◽

Isocitrate Dehydrogenase ◽

Ex Vivo ◽

Wild Type ◽

Atomic Force

Υπόβαθρο – Σκοπός: Οι μηχανικές ιδιότητες των γλοιωμάτων του εγκεφάλου αποτελούν μία καινοτόμο πηγή ανάπτυξης θεραπευτικών και διαγνωστικών προσεγγίσεων. Η παρούσα διδακτορική διατριβή διερεύνησε την ύπαρξη διαφοράς στην ελαστικότητα μεταξύ των ιστού γλοιωμάτων του εγκεφάλου και της περινεοπλασματικής λευκής ουσίας σε χειρουργικά ιστοτεμάχια. Επιπλέον, διερεύνησε την ύπαρξη διαφοράς στην ελαστικότητα μεταξύ γλοιωμάτων διαφορετικού βαθμού κακοήθειας σύμφωνα με το σύστημα ταξινόμησης του Παγκοσμίου Οργανισμού Υγείας (ΠΟΥ), καθώς και της επίδρασης των παθολογοανατομικών χαρακτηριστικών και του μηχανικού προεγκλιματισμού στην ελαστικότητα του νεοπλάσματος και της λευκής ουσίας. Μέθοδοι: Το μέτρο ελαστικότητας μετρήθηκε ex vivo σε νωπά χειρουργικά ιστοτεμάχια που συλλέχθηκαν κατά τη διάρκεια κρανιοτομίας από το νεόπλασμα και την περινεοπλασματική λευκή ουσία 17 ασθενών που έπασχαν από υπερσκηνίδιο γλοίωμα. Τα δοκίμια που προέκυψαν από τον τεμαχισμό των ιστοτεμαχίων με μικροτόμο ταλάντωσης υποβλήθηκαν σε τυπική μονοτονική και σε επαναλαμβανόμενη παραμόρφωση χρησιμοποιώντας νανοδιείσδυση με μικροσκόπιο ατομικών δυνάμεων (atomic force microscope / AFM). Πραγματοποιήθηκε σύγκριση του μέτρου ελαστικότητας μεταξύ του ιστού των γλοιωμάτων και της λευκής ουσίας και μεταξύ γλοιωμάτων διαφορετικού βαθμού κακοήθειας. Εκτιμήθηκε η επίδραση χαρακτηριστικών των διάχυτων γλοιωμάτων, όπως οι μεταλλάξεις της οικογενείας των γονιδίων της ισοκιτρικής αφυδρογονάσης (isocitrate dehydrogenase / IDH) και ο βαθμός κακοήθειας κατά ΠΟΥ, της ηλικίας και του προεγκλιματισμού στην ελαστικότητα του νεοπλάσματος και της περινεοπλασματικής λευκής ουσίας με χρήση γραμμικών μοντέλων μικτών επιδράσεων. Αποτελέσματα: Το μέτρο ελαστικότητας δε διέφερε σημαντικά μεταξύ του ιστού των γλοιωμάτων και της περινεοπλασματικής λευκής ουσίας (p = 0,5), ούτε μεταξύ γλοιωμάτων διαφορετικού βαθμού κακοήθειας (p = 0,2). Κατά τη μελέτη χαρακτηριστικών των διαχύτων γλοιωμάτων με τυπική μονοτονική καταπόνηση, οι ιστοί από ασθενείς με wild-type IDH ήταν περισσότερο εύκαμπτοι από αυτούς με μεταλλάξεις της IDH μεταξύ περιστατικών βαθμού κακοήθειας III (p = 0,0496), αλλά παρόμοιοι σε ελαστικότητα με περιπτώσεις μεταλλάξεων της IDH σε περιστατικά με βαθμό κακοήθειας II (p = 0,48). Το γλοίωμα βρέθηκε μη σημαντικά πιο εύκαμπτο από τον παρακείμενο εγκεφαλικό ιστό σε περιστατικά βαθμού κακοήθειας III (p = 0,07) και παρόμοιο σε ελαστικότητα με την περινεοπλασματική λευκή ουσία σε περιστατικά βαθμού κακοήθειας II (p = 0,49) και IV (p = 0,59). Κατά την επαναλαμβανόμενη καταπόνηση, τόσο ο ιστός του γλοιώματος (p = 0,002) όσο και ο παρακείμενος εγκέφαλος (p = 0,003) αρχικά παρουσίασαν σκλήρυνση, που ακολουθήθηκε από χαλάρωση. Η σκλήρυνση αναστράφηκε πλήρως στην περινεοπλασματική λευκή ουσία και το μέτρο ελαστικότητας επανήλθε στις αρχικές τιμές (p = 0,94), αλλά μόνο μερικώς στο νεοπλασματικό ιστό (p = 0,015). Συμπεράσματα: Η ελαστικότητα του ιστού γλοιωμάτων και παρακειμένου εγκεφάλου αποτελεί ένα φαινοτυπικό χαρακτηριστικό στενά συνδεδεμένο με τα ιστοπαθολογικά γνωρίσματα των διάχυτων γλοιωμάτων. Θα πρέπει να διερευνηθούν περαιτέρω πηγές ετερογένειας στις τοπικές μετρήσεις εξατομικευμένα, αλλά και μεταξύ ομάδων ασθενών.

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Case 25: Primary Diagnosis of an Isocitrate Dehydrogenase (IDH) Wild-Type Glioma

10.1007/978-3-030-83598-9_25 ◽

2021 ◽

pp. 125-128

Author(s):

Nathalie L. Albert ◽

Bogdana Suchorska ◽

Adrien Holzgreve ◽

Marcus Unterrainer

Keyword(s):

Isocitrate Dehydrogenase ◽

Primary Diagnosis ◽

Wild Type

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The prognostic significance of wild-type isocitrate dehydrogenase 2 (IDH2) in breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-019-05459-7 ◽

2019 ◽

Vol 179 (1) ◽

pp. 79-90 ◽

Cited By ~ 3

Author(s):

Abrar I. Aljohani ◽

Michael S. Toss ◽

Sasagu Kurozumi ◽

Chitra Joseph ◽

Mohammed A. Aleskandarany ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Isocitrate Dehydrogenase ◽

Ductal Carcinoma ◽

Tumour Size ◽

Prognostic Significance ◽

Wild Type ◽

Hormonal Receptor ◽

Isocitrate Dehydrogenase 2 ◽

Receptor Negativity

Abstract Background Lymphovascular invasion (LVI) is a prerequisite step in breast cancer (BC) metastasis. We have previously identified wild-type isocitrate dehydrogenase 2 (IDH2) as a key putative driver of LVI. Thus, we explored the prognostic significance of IDH2 at transcriptome and protein expression levels in pre-invasive and invasive disease. Methods Utlising tissue microarrays from a large well annotated BC cohort including ductal carcinoma in situ and invasive breast cancer (IBC), IDH2 was assessed at the transcriptomic and proteomic level. The associations between clinicopathological factors including LVI status, prognosis and the expression of IDH2 were evaluated. Results In pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively. High expression of IDH2 either in mRNA or in protein levels was associated with poor patient’s outcome in both DCIS and IBC. Multivariate analysis revealed that IDH2 protein expression was an independent risk factor for shorter BC specific-survival. Conclusion Further functional studies to decipher the role of IDH2 and its mechanism of action as a driver of BC progression and LVI are warranted.

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