von Willebrand Factor Gene Expression in Primary Lower Grade Glioma: Mutually Co-Occurring Mutations in von Willebrand Factor, ATRX, and TP53

BACKGROUND: Venous thromboembolism is a common complication in patients with glioma. The clotting factor von Willebrand factor (VWF) is a highly adhesive procoagulant molecule that mediates platelet adhesion to endothelial and subendothelial surfaces. In the current analysis, we examined The Cancer Genome Atlas (TCGA) data to assess the VWF gene in patients with lower grade gliomas. METHODS: For newly diagnosed gliomas, we evaluated the association between VWF and overall survival in the Genomic Data Commons TCGA Lower Grade Glioma (LGG) dataset in TCGA. Simple statistics were calculated to identify patterns of mutual exclusivity or co-occurrence of VWF mutations. For each pair of query genes an odds ratio was calculated that indicates the likelihood that the mutations in the two genes are mutually exclusive or co-occurrent across the selected cases. To determine whether the identified relationship was significant for a gene pair, Fisher's exact test was performed. RESULTS: Lower grade gliomas with less VWF gene expression had significantly better survival than those with more VWF gene expression (hazard ratio 0.64, 95% confidence interval 0.44 to 0.92, p=0.015 log rank test). When we analyzed the data with Cox regression, VWF expression had a significant effect on survival (p=0.02) that was unrelated to the effect of IDH1 expression (p=0.062), TP53 expression (p=0.135), independent of ATRX expression (p=0.021) and histology (astrocytoma versus oligoastrocytoma and oligodendroglioma, p=0.002). VWF mutations significantly co-occur with mutations in TP53 and ATRX (p<0.001). CONCLUSION: The deleterious prognostic effect of VWF expression and its co-occurrent mutations with TP53 and ATRX in lower grade gliomas are not surprising, given VWF's role in other cancers. Therefore, VWF gene expression may be a clinically important risk marker in lower grade glioma.