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.

Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism

“…In univariable time‐to‐VTE regression, the IDH1 mutation predicted a lower risk of VTE (hazard ratio [HR] = 0.11; 95% CI, 0.01–0.80; P = 0.029), and this prevailed after multivariable adjustment for glioblastoma and age (Models #1 and #2, Table ). Thus, these clinical data externally validate previous findings demonstrating that mutant IDH1 is a predictor of low VTE risk in patients with primary brain tumors . Based on a mouse model, Unruh et al .…”

“…Based on a mouse model, Unruh et al . proposed that IDH1 mutation leads to decreased serum calcium levels with subsequent inhibition of platelet activation, thereby preventing VTE . However, we were not able to confirm a statistically significant association between IDH1 status and serum calcium concentrations in primary brain tumor patients (Table ).…”

“…The authors suggested that the risk of VTE in IDH1 mutant glioma patients is reduced by the inhibitory effect of D‐2‐HG on platelet aggregation. Interestingly, D‐2‐HG is an oncometabolite that is associated with DNA hypermethylation of several genes, including coagulation‐associated genes such as tissue factor (TF) .…”

The Microenvironmental Landscape of Brain Tumors

“…Similarly, we expect that major insights will come from a detailed comparison of how distinct molecular subtypes or genetic drivers in cancer cells may differentially sculpt their microenvironment during the course of cancer progression, as already indicated from several studies discussed herein (Miroshnikova et al, 2016; Osswald et al, 2015; Phoenix et al, 2016; Unruh et al, 2016). Indeed, there are genetic subsets of glioma that do display efficacy to standard of care cytotoxic therapy, for example, those with mutant IDH, or co-deletion of 1p and 19q in oligodendrogliomas.…”

Cancer‐associated thrombosis: The search for the holy grail continues

“…A recent study has investigated whether patients with wild‐type IDH1/2 glioblastoma are more likely to develop VTE. Interestingly, patients harboring IDH1/2 mutations did not develop VTE neither in a discovery nor in a validation cohort, both consisting of approximately 150 patients 56. Furthermore, only 2% of the tumors with IDH1/2 mutation showed intratumoral microthrombi versus 86% in wild‐type IDH1/2 tumors.…”