Microarray Expression Data Identify DCC as a Candidate Gene for Early Meningioma Progression

Abstract

Meningiomas are the most common primary brain tumors bearing in a minority of cases an aggressive phenotype. Although meningiomas are stratified according to their histology and clinical behavior, the underlying molecular genetics predicting aggressiveness are not thoroughly understood. We performed whole transcript expression profiling in 10 grade I and four grade II meningiomas, three of which invaded the brain. Microarray expression analysis identified deleted in colorectal cancer (DCC) as a differentially expressed gene (DEG) enabling us to cluster meningiomas into DCC low expression (3 grade I and 3 grade II tumors), DCC medium expression (2 grade I and 1 grade II tumors), and DCC high expression (5 grade I tumors) groups. Comparison between the DCC low expression and DCC high expression groups resulted in 416 DEGs (p-value < 0.05; fold change > 2). The most significantly downregulated genes in the DCC low expression group comprised DCC, phosphodiesterase 1C (PDE1C), calmodulin-dependent 70kDa olfactomedin 2 (OLFM2), glutathione S-transferase mu 5 (GSTM5), phosphotyrosine interaction domain containing 1 (PID1), sema domain, transmembrane domain (TM) and cytoplasmic domain, (semaphorin) 6D (SEMA6D), and indolethylamine N-methyltransferase (INMT). The most significantly upregulated genes comprised chromosome 5 open reading frame 63 (C5orf63), homeodomain interacting protein kinase 2 (HIPK2), and basic helix-loop-helix family, member e40 (BHLHE40). Biofunctional analysis identified as predicted top upstream regulators beta-estradiol, TGFB1, Tgf beta complex, LY294002, and dexamethasone and as predicted top regulator effectors NFkB, PIK3R1, and CREBBP. The microarray expression data served also for a comparison between meningiomas from female and male patients and for a comparison between brain invasive and non-invasive meningiomas resulting in a number of significant DEGs and related biofunctions. In conclusion, based on its expression levels, DCC may constitute a valid biomarker to identify those benign meningiomas at risk for progression.

RNA-seq transcriptome analysis of formalin fixed, paraffin-embedded canine meningioma

“…Other underexpressed genes have roles in cell adhesion. For instance, COL8A1 was identified by microarray analysis to be down-regulated in meningiomas, [ 56 , 66 ]. In addition, in our underexpressed gene cohort, GO enrichment analysis (biological process) identifies a number of genes involved in various aspects of regulation of cell adhesion, cell-cell adhesion, and cell- substrate or -matrix adhesion.…”

Non-circadian aspects of BHLHE40 cellular function in cancer

“…Grade I meningiomas are not aggressive but Grade II malignancies are known to infiltrate the surrounding brain tissue. A study that classified these tumors according to the expression of the tumor suppressor gene deleted in colorectal cancer (DCC), whose loss marks the aggressiveness of the meningiomas, showed that the expression of BHLHE40 was significantly upregulated in the DCC low (highly aggressive) tumors [76]. Taken together, these studies demonstrate that in all subtypes of brain carcinoma, tumor aggression is associated with an increase in the expression of BHLHE40.…”

In situ characterization of stem cells-like biomarkers in meningiomas

“…Previously, we published gene expression profiles for most of the meningioma patients’ tissues collected for our cohort [ 64 , 65 ], as well as for their corresponding cell lines [ 22 ]. For this work, we aimed to determine the hetero-dynamic characteristics of MCSCs in situ and identify differential patterns associated with grades II/III tumors.…”