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

Hans-Juergen Schulten,Deema Hussein,Sajjad Karim,Jaudah Al-Maghrabi,Mona Al-Sharif,Saleh S Baeesa,Awatif Jamal,Fahad Al-Ghamdi,Mohammed Bangash,Adeel Chaudhary,Mohammed Al-Qahtani,Fatima Al-Adwani,Aamir Ahmad

doi:10.1371/journal.pone.0153681

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.

Highlights

Meningiomas arise from arachnoidal cap cells of the arachnoidal membrane and are the most common intracranial neoplasms representing 20–35% of all primary brain tumors [1]
By utilizing whole transcript oligonucleotide arrays, we identified deleted in colorectal cancer (DCC) as a candidate gene for tumor progression in grade I and II meningiomas using an initial multiple group comparison that was performed on each meningioma against the brain normal (BN) samples which served as control set
Subsequent grouping of the meningiomas according to their DCC expression levels resulted in a set of 416 differentially expressed gene (DEG) between the DCC low expression and DCC high expression groups and the former one included the more aggressive tumors with the exception of one brain invasive meningioma that was categorized as a DCC medium expression tumor

Summary

Introduction

Meningiomas arise from arachnoidal cap cells of the arachnoidal membrane and are the most common intracranial neoplasms representing 20–35% of all primary brain tumors [1]. The well established tumor suppressor function of DCC is a result of its capacity to induce apoptosis as a dependence receptor for netrin-1 in case a ligand-receptor binding is interfered or the ligand is not present. This was demonstrated in vivo in netrin-1 knockout mice revealing that regulation of apoptosis is depending on the availability of netrin-1 for DCC [10, 11]. In different histological types of gliomas, a number of mechanisms has been described that alter DCC expression on the transcriptional or protein level that in case of transcriptional downregulation or negative immunoreactivity is related to high grade and progressive tumors [17,18,19]. As in our study, have been successfully used in other microarray expression studies on meningiomas to detect tumor-related gene profiles [20, 21]

Material and Methods

Results

I I II

Discussion