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

Abstract

Essentials Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging.Patients with IDH1 wildtype and high podoplanin expression have a 6‐month VTE risk of 18.2%.Patients with IDH1 mutation and no podoplanin expression have a 6‐month VTE risk of 0%. IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive. SummaryBackgroundVenous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk.ObjectivesTo investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development.Patients/MethodsIn a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2‐year follow‐up.ResultsAll brain tumors that expressed podoplanin to a medium‐high extent showed also an IDH1 wild‐type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild‐type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6‐month risk 18.2% vs. 0%).Conclusions IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild‐type tumors is strongly linked to podoplanin expression levels.

Low Systemic Levels of Chemokine C-C Motif Ligand 3 (CCL3) are Associated with a High Risk of Venous Thromboembolism in Patients with Glioma

“…The inverse association of CCL3 with VTE in our study was independent of previously described VTE risk factors in brain tumors [19][20][21][22][23]. For example, a higher glioma grade as well as distinct local tumor characteristics, such as the upregulation of podoplanin expression on tumor cells, are associated with a higher VTE risk [19].…”

“…For example, a higher glioma grade as well as distinct local tumor characteristics, such as the upregulation of podoplanin expression on tumor cells, are associated with a higher VTE risk [19]. Furthermore, an IDH1 wildtype status is linked to a higher risk of VTE, while patients with an IDH1 mutation have a very low VTE risk [20,21]. In addition, laboratory parameters, such as a low platelet count, a high leukocyte count and higher soluble P-selectin and D-Dimer levels, have been reported to be associated with a higher VTE risk in a larger cohort of patients with glioma [22].…”

“…Patients who underwent surgery or radiotherapy within the past 2 weeks before recruitment, and/or chemotherapy within the past 3 months were ineligible. Data on IDH1 mutation status and podoplanin expression in the tumor tissue as well as sP-selectin and D-dimer levels in the blood were available from our previous investigations [19,21,22,52,53].…”

“…Primary brain tumors belong to those tumor entities with a particularly high VTE risk, and 10% to 20% of the patients develop VTE during the course of the disease [18]. Previously, several risk factors have been described [19][20][21][22][23]. However, the impact of anti-and pro-inflammatory cytokines on thromboembolic events in patients with glioma has not been evaluated in detail.…”

Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis

“…IDH1 mutant tumors exhibited low level of TF immunostaining, and their corresponding levels of EV-associated TF activity (TF-MPs) in blood showed a tendency toward reduction, relative to the IDH wild-type disease. 56 In another subsequent study, it was found that combined low PDPN and IDH1 mutation signify the lowest VTE risk among all GBM patients, 90 even though PDPN is likely downregulated by mutant IDH1 at the level of the epigenome. 4,40 The molecular landscapes of pediatric brain tumors are vastly different than those in adults and are increasingly well characterized, 78,[91][92][93] but they are infrequently discussed in the context of CAT.…”