Microarray Expression Data Identify <i>DCC</i> as a Candidate Gene for Early Meningioma Progression

<div><p>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 (<i>DCC</i>) as a differentially expressed gene (DEG) enabling us to cluster meningiomas into <i>DCC</i> low expression (3 grade I and 3 grade II tumors), <i>DCC</i> medium expression (2 grade I and 1 grade II tumors), and <i>DCC</i> high expression (5 grade I tumors) groups. Comparison between the <i>DCC</i> low expression and <i>DCC</i> high expression groups resulted in 416 DEGs (<i>p</i>-value < 0.05; fold change > 2). The most significantly downregulated genes in the <i>DCC</i> low expression group comprised <i>DCC</i>, phosphodiesterase 1C (<i>PDE1C</i>), calmodulin-dependent 70kDa olfactomedin 2 (<i>OLFM2</i>), glutathione S-transferase mu 5 (<i>GSTM5</i>), phosphotyrosine interaction domain containing 1 (<i>PID1</i>), sema domain, transmembrane domain (TM) and cytoplasmic domain, (semaphorin) 6D (<i>SEMA6D</i>), and indolethylamine N-methyltransferase (<i>INMT</i>). The most significantly upregulated genes comprised chromosome 5 open reading frame 63 (<i>C5orf63</i>), homeodomain interacting protein kinase 2 (<i>HIPK2</i>), and basic helix-loop-helix family, member e40 (<i>BHLHE40</i>). 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, <i>DCC</i> may constitute a valid biomarker to identify those benign meningiomas at risk for progression.</p></div

The predicted top upstream regulators in the comparison group female <i>vs</i>. male meningioma patients are tacrolimus, glutathione, ITPR, (E)-2,3',4,5'-tetramethoxystilbene, and SLC39A4 with a <i>p</i>-value of overlap of 1.16E-03, 1.55E-03, 2.02E-03, 2.02E-03, and 2.02E-03, respectively.

<p>Target genes are <i>APOD</i>, <i>KLRC4-KLRK1</i>/<i>KLRK1</i>, <i>MYH10</i>, <i>TNC</i>, <i>SLC7A11</i>, <i>CYP1B1</i>, and <i>NELL1</i>. Upregulated and downregulated genes in red and blue color, respectively. Asterisk indicates a gene that is represented in the dataset by more than one transcript.</p

Unsupervised hierarchical cluster analysis of 416 genes that were differentially expressed (<i>p</i>-value < 0.05; fold change > 2.0) between the three <i>DCC</i> expression groups.

<p>BN samples are included in cluster analysis. A number of genes is represented by more than one transcript. Meningiomas are clustering into two main branches, one of which contains the <i>DCC</i> low expression samples and a <i>DCC</i> medium expression sample that was a brain invasive case. Color scheme bar indicates comparably higher and lower expression values in red and blue color, respectively. Color scheme for samples: yellow, <i>DCC</i> low expression; green, <i>DCC</i> medium expression; orange, <i>DCC</i> high expression; BN samples, red.</p

The predicted top regulator effects network with a consistency score of 8.489 in the <i>DCC</i> low <i>vs</i>. <i>DCC</i> high expression comparison.

<p>Upstream regulators NFkB, PIK3R1, and CREBBP target a number of DEGs including <i>MMP2</i>, <i>SERPINE2</i>, <i>DOK5</i>, <i>SLC2A5</i>, <i>FST</i>, <i>TGM2</i>, <i>NR4A3</i>, <i>TGFB3</i>, <i>BCL2</i>, <i>NCAM1</i>, <i>TLR2</i>, <i>AR</i>, <i>CTGF</i>, <i>VEGFA</i>, <i>CYR61</i>, <i>VCAM1</i>, and <i>GDF15</i>. Connected downstream functions are entitled adhesion of leukemia cell lines, differentiation of cells, sprouting (including cell morphological characteristics), cell viability, and cell movement of phagocytes.</p

The predicted top regulator effects network with a consistency score of 13.0 in the brain invasive <i>vs</i>. non-invasive meningioma dataset.

<p>Effector molecules IFNG, IL1B, and TNF target a number of DEGs including <i>OCLN</i>, <i>FLT1</i>, <i>CYBB</i>, <i>MCAM</i>, <i>RGS1</i>, <i>ITGA4</i>, <i>SPP1</i>, <i>FCGR1A</i>, <i>FCGR2A</i>, <i>TLR2</i>, <i>THBS1</i>, <i>C3</i>, <i>SELPLG</i>, and <i>FCGR3A</i>/<i>FCGR3B</i>. Connected downstream functions are entitled, cell movement of myeloid cells, adhesion of blood cells, engulfment of cells, response of phagocytes, response of myeloid cells, binding of professional phagocytic cells, and recruitment of cells. Upregulated and downregulated genes in red and blue color, respectively. Asterisk indicates a gene that is represented in the dataset by more than one transcript.</p

PCA scatter plot as a dimensional measure for the similarity of the expression profiles of samples (colored dots).

<p>Ellipsoids represent the 95% confidence interval and are a measure for the distance of relationships between samples of a group. Green, <i>DCC</i> low expression; purple, <i>DCC</i> medium expression; blue, <i>DCC</i> low expression; red, normal brain samples (BN).</p