Tissue Factor as a Key Determinant of IDH1 Mutant versus IDH1 Wild-type Glioma Thrombosis and Malignancy

Infiltrative gliomas are the most common type of primary brain tumor in adults, causing over 17,000 deaths in the United States every year. However, advances in our understanding of glioma genetics are providing opportunities to improve the care of patients with these tumors. Approximately 20-30% of infiltrative gliomas contain mutations in isocitrate dehydrogenase 1 (IDH1mut). IDH1mut causes global DNA hypermethylation, which contributes to gliomagenesis. Yet, IDH1mut gliomas are significantly less aggressive than gliomas lacking this mutation. It has remained unclear how DNA hypermethylation leads to this unique phenotype. Gliomas often produce blood clots (thrombi) within the tumor and throughout the peripheral circulation. These thrombi have long been known to be predictors of poor outcome. We recently reported that IDH1mut gliomas produce far fewer thrombi; our data strongly indicate that methylation-induced suppression of F3, the gene encoding Tissue Factor (TF), is the reason why. TF is a powerful procoagulant that, when produced and released by cancers, causes venous thromboemboli (VTE). This debilitating phenomenon occurs in ~25% of glioma patients, but never when IDH1mut is present. In addition to triggering thrombosis, TF binds and activates protease-activated receptor 2 (PAR2), a transmembrane receptor expressed by cancer cells that signals through multiple intracellular pathways to promote tumor malignancy. Our data show that: (1) among all genes that directly participate in blood clotting, F3 mRNA levels have the strongest inverse relationship with IDH1mut; (2) F3 methylation is significantly higher in IDH1mut gliomas than IDH1wt gliomas; (3) TF protein levels are lower in IDH1mut gliomas than IDH1wt gliomas; (4) circulating TF is lower in patients with IDH1mut gliomas than IDH1wt gliomas; (5) high circulating TF correlates with increased VTE risk; (6) patient-derived glioma cells with endogenous IDH1mut produce smaller and fewer thrombi than IDH1wt gl