Mutant IDH1 and thrombosis in gliomas.
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.
Department of Neurosurgery, Northwestern University, Tarry 2-705, 300 East Superior Street, Chicago, IL, 60611, USA.
Dusten
D
Unruh
Department of Pathology, University of Kentucky, Lexington, KY, USA.
Steven R
SR
Schwarze
Department of Neurosurgery, University of Kentucky, Lexington, KY, USA.
Laith
L
Khoury
Department of Pathology, New York University, New York, NY, USA.
Cheddhi
C
Thomas
Department of Neurosurgery, Northwestern University, Tarry 2-705, 300 East Superior Street, Chicago, IL, 60611, USA.
Meijing
M
Wu
Department of Biostatistics, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Li
L
Chen
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA.
Rui
R
Chen
Department of Pathology, University of Kentucky, Lexington, KY, USA.
Yinxing
Y
Liu
Department of Neurology, Northwestern University, Chicago, IL, USA.
Margaret A
MA
Schwartz
Department of Neurosurgery, Northwestern University, Tarry 2-705, 300 East Superior Street, Chicago, IL, 60611, USA.
Christina
C
Amidei
Department of Neurology, Northwestern University, Chicago, IL, USA.
Priya
P
Kumthekar
Department of Neurosurgery, New York University, New York, NY, USA.
Carolina G
CG
Benjamin
University of Kentucky, Lexington, KY, USA.
Kristine
K
Song
University of Kentucky, Lexington, KY, USA.
Caleb
C
Dawson
Department of Radiology, New York University, New York, NY, USA.
Joanne M
JM
Rispoli
Department of Radiology, New York University, New York, NY, USA.
Girish
G
Fatterpekar
Department of Neurosurgery, New York University, New York, NY, USA.
John G
JG
Golfinos
Department of Neurosurgery, New York University, New York, NY, USA.
Douglas
D
Kondziolka
Department of Pediatrics, New York University, New York, NY, USA.
Matthias
M
Karajannis
Department of Neurosurgery, New York University, New York, NY, USA.
Donato
D
Pacione
Department of Pathology, New York University, New York, NY, USA.|Department of Neurosurgery, New York University, New York, NY, USA.
David
D
Zagzag
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA.
Thomas
T
McIntyre
Department of Pathology, New York University, New York, NY, USA.
Matija
M
Snuderl
Department of Neurosurgery, Northwestern University, Tarry 2-705, 300 East Superior Street, Chicago, IL, 60611, USA. craig.horbinski@northwestern.edu.|Department of Pathology, Northwestern University, Chicago, IL, USA. craig.horbinski@northwestern.edu.
Craig
0000-0001-8340-9992
C
Horbinski
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000429:Alcohol Oxidoreductases / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D000001:Calcimycin / Q000494:pharmacology; D061207:Calcium Ionophores / Q000494:pharmacology; D015331:Cohort Studies; D005260:Female; D005910:Glioma / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology
D000970:Antineoplastic Agents; D061207:Calcium Ionophores; D000001:Calcimycin; D013925:Thromboplastin; D000429:Alcohol Oxidoreductases; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C021379:D-2-hydroxyacid dehydrogenase; D013917:Thrombin
D-2-hydroxyglutarate; Glioma; Isocitrate dehydrogenase; Platelet; Thrombosis; Tissue factor
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