The Accuracy of Survival Time Prediction for Patients with Glioma Is Improved by Measuring Mitotic Spindle Checkpoint Gene Expression

Abstract

Identification of gene expression changes that improve prediction of survival time across all glioma grades would be clinically useful. Four Affymetrix GeneChip datasets from the literature, containing data from 771 glioma samples representing all WHO grades and eight normal brain samples, were used in an ANOVA model to screen for transcript changes that correlated with grade. Observations were confirmed and extended using qPCR assays on RNA derived from 38 additional glioma samples and eight normal samples for which survival data were available. RNA levels of eight major mitotic spindle assembly checkpoint (SAC) genes (BUB1, BUB1B, BUB3, CENPE, MAD1L1, MAD2L1, CDC20, TTK) significantly correlated with glioma grade and six also significantly correlated with survival time. In particular, the level of BUB1B expression was highly correlated with survival time (p<0.0001), and significantly outperformed all other measured parameters, including two standards; WHO grade and MIB-1 (Ki-67) labeling index. Measurement of the expression levels of a small set of SAC genes may complement histological grade and other clinical parameters for predicting survival time.

A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells

“…Consistent with prior reports, we found CDC20 mRNA is significantly elevated in glioblastomas compared to normal brain (Figure 5A) (Bie et al, 2011; Marucci et al, 2008). We then assessed CDC20 expression in the four TCGA-based molecular subtypes—Proneural, Mesenchymal, Classical, and Neural—and found the Proneural subtype demonstrated significantly higher CDC20 expression compared to the other subtypes (Figure 5B) (Verhaak et al, 2010).…”

“…CDC20-APC has been viewed as a potential strategic target in several human cancers (Wang et al, 2015). CDC20 mRNA is elevated in glioblastoma compared to low-grade gliomas, and CDC20 immunoreactivity in gliomas correlates with pathological grade, but little is known about the biological roles of CDC20-APC in glioblastoma (Bie et al, 2011; Marucci et al, 2008). Recent studies have revealed unexpected non-mitotic roles for CDC20-APC in the developing mammalian brain, indicating CDC20-APC executes functions beyond the cell cycle (Kim et al, 2009; Puram et al, 2011; Yang et al, 2009).…”

Identification of Genomic Targets of Transcription Factor Aebp1 and its role in Survival of Glioma Cells

“…Cell-cycle regulator CDC20 that is often upregulated in several malignancies (30) and indirectly regulated by p53, is downregulated under AEBP1 downregulated condition, whereas p53 itself is upregulated. Interestingly CDC20 has also been associated with prognostic behavior of glioma patients (37). Again CDK6, an established marker associated with GBM (38,39), is also affected by AEBP1 downregulation.…”

Molecular Pathways: Regulation and Targeting of Kinetochore–Microtubule Attachment in Cancer

“…Loss of SAC function is a common explanation proffered for increased chromosome instability and aneuploidy in cancers (25-27). This notion that loss of SAC activity promotes tumorigenesis has found support in studies of certain cancers (25,26) and model systems (e.g., mouse knockouts of certain SAC genes) (23, 28). However, loss of function mutations in SAC genes are rare in cancers (27), and many late-stage cancers exhibit high SAC gene expression (29, 30), suggesting hyperactivity (30,31).…”