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.

Measles may be a Risk Factor for Malignant Brain Tumors

BACKGROUND: A possible risk factor for brain tumor might be measles, since late neurologic sequelae are part of measles pathology. Subacute sclerosing panencephalitis, a devastating neurologic illness, is prone to develop years after measles infection. METHODS: Because measles damage to the brain might increase the risk of brain tumor, we examined the relationship of measles incidence in 1960 and brain tumor incidence in 50 US States and the District of Columbia, 2004-2007. Data on number of cases of measles by state in 1960 are from the Morbidity and Mortality Weekly Report. In 1960 measles was a childhood illness. We calculated measles incidence by obtaining the population of each state from the 1960 US Census and then age adjusting our results to the cumulative percent of the state population under age 21, since this would have been the measles-infected group. Data on the percentage white population by state are from the US Census (www.census.gov). Age-adjusted incidence (to the 2000 US standard population) of brain tumors is from the Central Brain Tumor Registry of the United States 2011 report. RESULTS: There was a significant correlation between 1960 measles incidence and incidence of malignant brain tumors in persons 20 and older in 2004-2007 (r=0.321, p=0.026). Because glioblastoma is more frequent in whites and males, multivariate linear regression was performed with tumor incidence as the dependent variable, measles incidence, percent white population, and sex ratio by state as independent variables. Measles incidence was significantly correlated with malignant brain tumor incidence (beta=0.361, p<0.001) and independent of the effect of race (beta=0.734, p<0.001) and sex ratio m/f (beta=-0.478, p<0.001). There was no correlation of measles incidence with brain tumor incidence in persons younger than 20. CONCLUSION: Inflammation is a critical component of tumor development. The inflammation of measles-induced subacute sclerosing panencephalitis, even subclinical cases, could well promote tumor formation, since many tumors arise from sites of infection, chronic irritation and inflammation.