Mutant IDH1 and thrombosis in gliomas

AbstractMutantisocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects ofIDH1 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, forIDH1 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-typeIDH1 gliomas, but not in patients with mutantIDH1 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 mutantIDH1 gliomas regardless of WHO grade (85 –90 % in wild-type versus 2–6 % in mutant), and were an independent predictor ofIDH1 wild-type status. Among all 35 coagulation-associated genes,F3 mRNA, encoding TF, showed the strongest inverse relationship withIDH1 mutations. MutantIDH1 gliomas hadF3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, met...
Source: Acta Neuropathologica - Category: Neurology Source Type: research