IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas

Abstract

BackgroundVascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades 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.MethodsGene 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 database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.ResultsGene 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 laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (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 upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.ConclusionIDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas

“…16 IDH wild type LGG vessels are molecularly distinct from the IDH1 mutated, therefore indicative of vascular remodeling and angiogenesis. 35 We believe more studies with large number of samples of multiple ethnicities are warranted before establishing NAMPT and SERPINE1 overexpression as a surrogate biomarker for adverse prognosis within IDH1 wild type LGG subgroup.…”

RNA processing genes characterize RNA splicing and further stratify lower-grade glioma

“…RNA plays crucial roles in biological functions in cells not only by passing genetic information from DNA to protein but also by regulating various biological processes (42). Dysregulation of RNA profiles, including hypoxia-associated gene sets (43), vascular gene sets (44), WNT/β-catenin pathway-related genes (45), genes in the NF-κB signaling pathway (46), microRNA (18), and long noncoding RNA (47), have been shown to play crucial roles in the malignant progression and prognosis of LGGs. Here, we highlight the stratification ability of RNA processing genes in LGGs.…”

Prognostic value of VEGFR2 immunoexpression in glioblastoma

“…[11] VEGF expression is higher in tumor areas that are under hypoxia [11] in which the hypoxia factor 1 (HIF1) is highly expressed. Hypoxia is related to neovascularization, [6] and angiogenesis is determined by VEGFR2 expression. [12] Thus, there is a relationship between the hypoxia and the expression of VEGF and its receptors.…”

“…[4,5] The association between an increase of gene expression related with hypoxia and neovascularization has been published. [6] This increased expression is more intense for wild-type IDH1 than for mutated IDH1. [6] GBs containing mutated IDH1 are less angiogenic, have smaller blood vessels, and are associated with less hypoxia than those containing wild-type IDH1.…”

“…[6] This increased expression is more intense for wild-type IDH1 than for mutated IDH1. [6] GBs containing mutated IDH1 are less angiogenic, have smaller blood vessels, and are associated with less hypoxia than those containing wild-type IDH1. [7] Increased hypoxia is associated to an increase in invasiveness, stem cell maintenance, treatment resistance, and angiogenesis.…”