Mutant IDH1 and thrombosis in gliomas

Abstract

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II–IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26–30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85–90 % in wild-type versus 2–6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

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Acknowledgments

CH was supported by the National Cancer Institute (K08CA155764). The authors thank Michael Gallagher for Fig. 5, Bernice Slone from the Kentucky Cancer Registry for outcome data, Dana Napier for histotechnical support, Sarah Langford for assistance with ionized calcium measurements, Dr. Sidney Whiteheart for advice on tail vein bleeding assays, Dr. Andrew Lane for the NMR experiment and manuscript comments, Kathleen McCortney for collecting the blood samples used in Fig. 3d and Table 2, and Dr. C. David James for manuscript comments. The University of Kentucky Biospecimen and Tissue Procurement, Biostatistics, and Redox Metabolism Shared Resource Facilities are supported by the Markey Cancer Center (P30CA177558). The Northwestern Nervous System Tumor Bank is supported by the Department of Neurological Surgery. Methylation profiling of brain tumors at NYU is supported by The Friedberg Charitable Foundation.

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Correspondence to Craig Horbinski.

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D. Unruh and S. R. Schwarze contributed equally to this study.

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Unruh, D., Schwarze, S.R., Khoury, L. et al. Mutant IDH1 and thrombosis in gliomas. Acta Neuropathol 132, 917–930 (2016). https://doi.org/10.1007/s00401-016-1620-7

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Keywords

  • Isocitrate dehydrogenase
  • D-2-hydroxyglutarate
  • Thrombosis
  • Glioma
  • Tissue factor
  • Platelet