Abstract
The clinical prognosis of patients with glioma is determined by tumor grades, but tumors of different subtypes with equal malignancy grade usually have different prognosis that is largely determined by genetic abnormalities. Oligodendrogliomas (ODs) are the second most common type of gliomas. In this study, integrative analyses found that distribution of TCGA transcriptomic subtypes was associated with grade progression in ODs. To identify critical gene(s) associated with tumor grades and TCGA subtypes, we analyzed 34 normal brain tissue (NBT), 146 WHO grade II and 130 grade III ODs by microarray and RNA sequencing, and identified a co-expression network of six genes (AURKA, NDC80, CENPK, KIAA0101, TIMELESS and MELK) that was associated with tumor grades and TCGA subtypes as well as Ki-67 expression. Validation of the six genes was performed by qPCR in additional 28 ODs. Importantly, these genes also were validated in four high-grade recurrent gliomas and the initial lower-grade gliomas resected from the same patients. Finally, the RNA data on two genes with the highest discrimination potential (AURKA and NDC80) and Ki-67 were validated on an independent cohort (5 NBTs and 86 ODs) by immunohistochemistry. Knockdown of AURKA and NDC80 by siRNAs suppressed Ki-67 expression and proliferation of gliomas cells. Survival analysis showed that high expression of the six genes corporately indicated a poor survival outcome. Correlation and protein interaction analysis provided further evidence for this co-expression network. These data suggest that the co-expression of the six mitosis-regulating genes was associated with malignant progression and prognosis in ODs.
Highlights
Oligodendrogliomas (ODs) are the second most common type of gliomas and classified as oligodendroglioma gradeII (OII), anaplastic oligodendroglioma grade III (OIII), oligoastrocytoma grade II (OAII) or anaplastic oligoastrocytoma grade III (OAIII), according to the World Health Organization (WHO) classification system [1]
We found that the high frequency of these markers is already present in ODII (75% in IDH1, 5.1% in IDH2 and 46.0% in LOH1p/19q) while the frequency does not increase in ODIII (61.6% in IDH1, 1.8% in IDH2 and 26.4% in LOH1p/19q)
The result suggests that they may not be associated with malignant progression from ODII–ODIII
Summary
Oligodendrogliomas (ODs) are the second most common type of gliomas and classified as oligodendroglioma gradeII (OII), anaplastic oligodendroglioma grade III (OIII), oligoastrocytoma grade II (OAII) or anaplastic oligoastrocytoma grade III (OAIII), according to the World Health Organization (WHO) classification system [1]. Many tumor suppressors located on chromosomal arms 1p/19q were identified by examining the comprehensive gene expression profiles [3, 4] These silencing genes by LOH1p/19q may play tumorigenic roles in ODs. Recently, isocitrate dehydrogenase 1/2 (IDH1/2) was shown to be mutated in up to 70%–80% of low-grade gliomas (grades II and III) [5]. IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) This mutation occurs at the arginine residue of the enzymes active site and causes a gain of function, leading to a reduction of α-KG to D-2-hydroxyglutarate (D-2HG) [6]. The TERT promoter mutation always occurred in the setting of patients with IDH1/2 mutation [9, 10] and this mutation highly correlated with upregulated TERT mRNA expression and tumor grade in adult gliomas [11, 12].
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