IDH-mutation Status is Associated with Distinct Vascular Gene Expression Signatures in Lower Grade Gliomas

Abstract

Background

Vascular gene expression patterns in lower grade gliomas (LGG, diffuse WHO grade II-III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH)-mutation status affects vascular phenotype.

Methods

Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the TCGA database. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grade II-IV gliomas and non-malignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

Results

Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of LAMA4 and ANGPT2 in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including up-regulation of ANGPT2 and SERPINH, connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased TGFβ and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was up-regulated by stimulation of endothelial cells with TGFβ2, VEGF or CoCl₂in vitro.

Conclusion

IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGF and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.