TMIC-13MUTANTIDH1/2SUPPRESSES LOCAL AND SYSTEMIC THROMBOSIS IN GLIOMA PATIENTS

Abstract

Mutations in isocitrate dehydrogenase 1 and 2 (mutIDH1/2) are common in gliomas, resulting in enzymes that produce D-2-hydroxyglutarate (D-2-HG). The effects of mutIDH1/2 on the microenvironment, including thrombosis, are not known. In discovery and validation cohorts of World Health Organization (WHO) grade II-IV gliomas from two institutions (total N = 317), microthrombi were present in 85-90% of wild-type gliomas but in only 2-6% of mutant gliomas (P < 0.0001), and their absence was an independent predictor of mutIDH1/2. Systemic hypercoagulation occurred in 25-30% of patients with wild-type IDH1/2 gliomas, but in 0% of patients with mutIDH1/2 gliomas (P < 0.0001). The prognostic strength of microthrombi was comparable to necrosis and microvascular proliferation, the current WHO criteria for a diagnosis of glioblastoma. In silico analysis of 428 gliomas from The Cancer Genome Atlas (TCGA) revealed that, in the coagulome, the mRNA with the strongest inverse relationship to mutIDH1/2 was F3, encoding tissue factor procoagulant (P = 1.06E-52). MutIDH1/2 gliomas in the TCGA also had significantly elevated F3 promoter methylation (P < 0.0001). In a separate tissue microarray containing 95 gliomas, mutIDH1/2 tumors showed dramatically reduced tissue factor protein expression (P < 0.0001). Additionally, D-2-HG inhibited human platelet aggregation by blocking intracellular calcium accumulation. In human in vitro and mouse in vivo models, mutIDH1 and D-2-HG lowered free serum calcium by up to 40% and markedly impaired coagulation (P < 0.0001). In sum, mutIDH1/2 enzymes have potent antithrombotic activity within gliomas and systemically. These findings have profound implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment and calcium homeostasis, and the pre-and postoperative management of these patients.