Meta-analysis of whole-genome gene expression datasets assessing the effects of IDH1 and IDH2 mutations in isogenic disease models

AbstractMutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are oncogenic drivers to a variable extent in several tumors, including gliomas, acute myeloid leukemia (AML), cholangiocarcinoma, melanoma, and thyroid carcinoma. The pathobiological effects of these mutations vary considerably, impeding the identification of common expression profiles. We performed an expression meta-analysis between IDH-mutant (IDHmut) and IDH-wild-type (IDHwt) conditions in six human and mouse isogenic disease models. The datasets included colon cancer cells, glioma cells, heart tissue, hepatoblasts, and neural stem cells. Among differentially expressed genes (DEGs), serine protease 23 (PRSS23) was upregulated in four datasets, i.e., in human colon carcinoma cells, mouse heart tissue, mouse neural stem cells, and human glioma cells. Carbonic anhydrase 2 (CA2) and prolyl 3-hydroxylase 2 (P3H2) were upregulated in three datasets, and SOX2 overlapping transcript (SOX2-OT) was downregulated in three datasets. The most significantly overrepresented protein class was termed intercellular signal molecules. An additional DEG set contained genes that were both up- and downregulated in different datasets and included oxidases and extracellular matrix structural proteins as the most significantly overrepresented protein classes. In conclusion, this meta-analysis provides a comprehensive overview of the expression effects of IDH mutations shared between different isogenic disease models. The generated dataset includes biomarkers, e.g., PRSS23 that may gain relevance for further research or clinical applications in IDHmut tumors.</jats:p

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

Demographic, histopathological, and <i>DCC</i> expression characteristics of 14 meningiomas.

Demographic, histopathological, and DCC expression characteristics of 14 meningiomas.</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

Expression of <i>DCC</i> exons in 14 meningiomas and three normal brain samples.

Upper panel, DCC exons are interrogated with 29 probes. Lower panel, hierarchical cluster analysis based on the DCC expression values reveals two main branches, one of which contains the six DCC low expression meningiomas. Based on the expression values (Table 1) the meningiomas were grouped into DCC high, DCC medium, and DCC low expression samples.</p

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

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