Abstract
Gliomas are classified by combining histopathologic and molecular features, including isocitrate dehydrogenase (IDH) status. Although IDH-wild-type diffuse astrocytic glioma (DAG) shows a more aggressive phenotype than IDH-mutant type, lack of knowledge regarding relevant molecular drivers for this type of tumor has hindered the development of therapeutic agents. Here, we examined human IDH-wild-type DAGs and a glioma mouse model with a mosaic analysis with double markers (MADM) system, which concurrently lacks p53 and NF1 and spontaneously develops tumors highly comparable with human IDH-wild-type DAG without characteristic molecular features of glioblastoma (DAG-nonMF). During tumor formation, enhancer of zeste homolog (EZH2) and the other polycomb repressive complex 2 (PRC2) components were upregulated even at an early stage of tumorigenesis, together with an increased number of genes with H3K27me3 or H3K27me3 and H3K4me3 bivalent modifications. Among the epigenetically dysregulated genes, frizzled-8 (Fzd8), which is known to be a cancer- and stem cell reprogramming-related gene, was gradually silenced during tumorigenesis. Genetic and pharmacologic inhibition of EZH2 in MADM mice showed reactivation of aberrant H3K27me3 target genes, including Fzd8, together with significant reduction of tumor size. Our study clarifies a pathogenic molecular pathway of IDH-wild-type DAG-nonMF that depends on EZH2 activity and provides a strong rationale for targeting EZH2 as a promising therapeutic approach for this type of glioma. SIGNIFICANCE: EZH2 is involved in the generation of IDH-wild-type diffuse astrocytic gliomas and is a potential therapeutic target for this type of glioma. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4814/F1.large.jpg.
Highlights
Gliomas represent approximately 80% of malignant central nervous system tumors
Characteristic molecular features of isocitrate dehydrogenase (IDH)-wild-type diffuse astrocytic glioma (DAG) Using the public database of the Cancer Genome Atlas (TCGA), we investigated the molecular profiles of IDH-wild-type DAGs (n 1⁄4 64 and n 1⁄4 13, DAG-MF and DAG-nonMF, respectively)
EGFR was the most commonly mutated gene with the highest mutation frequency and variant allele fraction (VAF) in IDH-wild-type DAGs-MF (40% and 55%), while p53 and NF1 were the genes with high mutation frequency and VAF in IDH-wild-type DAGs-nonMF (40% and 46%, 30% and 61%, respectively; Fig. 1C)
Summary
The World Health Organization (WHO) classification system subdivides diffuse astrocytic glioma (DAG) and oligodendroglioma into grade II to IV based on histopathologic findings [1, 2]. Recent comprehensive studies revealed that WHO grade II and III DAG and oligodendroglioma, called lower grade gliomas (LGG), are classified by combining histopathologic and molecular features including isocitrate dehydrogenase (IDH) status. Mutations in the IDH gene have been found in approximately 80% of LGGs, which show a characteristic feature of relatively favorable prognosis, while IDH-wild-type LGGs display an aggressive phenotype [3,4,5]. Among LGGs, all cases of oligodendroglioma exhibit IDH gene mutation, while DAGs exhibit either wild- or mutant-types IDH gene status. LGGs are considered to be divided into IDH-mutant DAGs or oligodendrogliomas (IDH-mutant LGG), or IDH-wild-type DAGs
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