Summary of main results (Table 2)
In the pioneering oligonucleotide microarray study on meningiomas by Watson and colleagues [
14], 15 meningiomas (WHO grade I,
n = 6; WHO grade II,
n = 6; WHO grade III,
n = 3) and three post mortem leptomeninges were studied. The main result was the detection of gene expression profiles associated with WHO grade subtypes (growth hormone receptors, endothelin receptor A, IGF2, IGFBP-7). Selected genes were confirmed using qRT-PCR.
Sasaki and colleagues [
15] aimed at comparing the transcriptomic profiles of original meningiomas (
n = 3; one of each WHO grade) and primary cultures of the same samples. They found that 51 genes were up-regulated > fivefold, and 19 genes were down-regulated by twofold or more in the primary cultures. The results were validated with qRT-PCR.
Fathallah-Shaykh and colleagues [
16] studied ten meningiomas and compared them with pooled post mortem brain RNA from the occipital lobes of four individuals. With their approach 364 genes were differentially expressed, and they found evidence of activation of different signaling pathways like Wnt, MAP kinase, PI3K, and notch. No validation of the findings with alternative approaches was performed.
In a study of 30 meningiomas (WHO grade I,
n = 13; WHO grade II,
n = 12; WHO grade III,
n = 5) Wrobel and colleagues [
17] investigated 2,600 genes using cDNA microarrays. The gene expression profiles of each category were compared with each other. The main finding was that 37 genes were decreased and 27 increases in grades II and II meningiomas compared with grade I. Compared with a pool of RNA from various human tissues (heart, spleen, placenta, kidney, skeletal muscle, liver, brain, and lung) a gene signature of the meningiomas was identified: PTGDS, CLU, BAD, MGP, LIG1, ANXA2, MMP12, VIM, TIMP1, and CCND1 were highly expressed in the meningiomas. Selected genes were validated with qRT-PCR, and for several candidates the results corroborated with those found by microarray. The authors concluded that the study showed that genes related to cell cycle regulation, cellular proliferation, as well as the IGF and WNT signaling pathways were up-regulated in grades II and III meningiomas. However, a main limitation of the study was the low number of cDNA probes, covering <10% of all human genes.
The aim of the study of Lusis et al. [
18] was to identify genetic events responsible for malignant progression of meningiomas. Using the Affymetrix U133A/B GeneChip Microarrays the authors searched for transcripts that were lost in grade III meningiomas compared with grade I. They found that approximately 40% of down-regulated genes in grade III meningiomas were located at chromosomes 1p and 14q. One of the candidates, the NDRG2 genes, was consistently down-regulated in all grade III meningiomas both at the mRNA and protein level, and that this was correlated with hypermethylation of the corresponding promoter.
As a part of a larger study of the genomics of spinal meningiomas Sayagues et al. [
19] performed gene expression profiling to compare spinal and intracranial meningiomas. They included seven spinal and 11 intracranial meningiomas in the study. The main result was differential expression of 1,555 genes, of which 35 genes showed the highest correlation (
r
2 > 0.7 or
r
2 < −0.7). Thirty of these had lower expression in the intracranial tumors, whereas the remaining five genes were up-regulated. Three genes were selected for qRT-PCR validation, and a significant correlation (
p < 0.001) with microarray expression was found for all genes (NR4A3, DUSP5, and HOXA5).
In the study of Carvalho et al. [
20] the purpose was to identify molecular signatures that characterize the different grades of meningiomas and molecular mechanisms driving meningioma tumorigenesis. They included 23 meningiomas (WHO grade I,
n = 8; WHO grade II,
n = 7; WHO grade III,
n = 8). Using SAM, the authors found 28 genes differentially expressed between grades I and II meningiomas, and no differential expression between grades II and III. A total of 1,212 genes were differentially expressed between grades I and III meningiomas. In an unbiased unsupervised cluster analysis the 23 meningiomas grouped in two branches. All grades I and grade III meningiomas were located in separate branches, and the authors thus designated each branch as “low proliferative” and “high proliferative”, respectively. The grade II meningiomas were located in both branches, three of seven in the low-proliferative group, and the remaining four in the high-proliferative group. A selection of genes were validated using qRT-PCR.
In 2008, our group [
21] published a microarray study on meningiomas of grades I (
n = 22) and II (
n = 5), where the aim was to study the gene expression profiles of meningiomas in comparison to progenitor meningioma tissue (arachnoid cells). Unsupervised cluster analysis of a filtered data set of 16,430 genes showed that five of seven fibrous meningiomas clustered together, while the remaining samples (meningothelial, transitional, and atypical) made no clear branching. As control tissue we used samples from the membranes of four arachnoid cysts (AC), and all these samples formed a separate cluster indicating a very homogeneous transcription profile. Using the
t test, we detected 20 genes that differentiated between meningiomas and ACs (
p < 4.3 × 10
−7), in which the tumor suppressor gene WWOX was down-regulated and the oncogene TYMS was up-regulated. We also found 20 genes separating fibrous from meningothelial meningiomas (
p < 1.1 × 10
−5), where DMD and BMPR1B were up-regulated in the fibrous, and RAMP1 was down-regulated in the meningothelial meningiomas. qRT-PCR was performed on a selection of genes and showed similar expression profiles as those generated using microarray analysis.
Since a recognized mechanism of meningioma initiation is irradiation, Lillehei et al. [
22] performed a microarray study of five radiation-induced meningiomas (RIM) and six spontaneous meningiomas to find unique genes behind this phenomenon. Interestingly, based on a microarray of 54,675 genes unsupervised hierarchical cluster analysis did not show separate clustering of RIMs and spontaneous meningiomas. Using a
t test to compare the gene expression profiles of RIMs and spontaneous meningiomas the authors found a small subset of 20 genes separating the two groups (
p < 0.001).
Hankins et al. [
23] studied the expression profiles of 12,000 genes in six meningiomas (WHO grade I) and four dural samples. By this approach, the authors found five up-regulated and 35 down-regulated genes in the meningiomas. The down-regulation of the DLC1 gene was confirmed with qRT-PCR and immunohistochemical staining. No evidence of CpG methylation of the corresponding promoter was found. The authors concluded that DLC1 may function as a tumor suppressor gene in meningiomas.
Claus and colleagues [
24] studied 31 samples from sporadic meningiomas (WHO grade I,
n = 25; WHO grade II,
n = 6) with the aim of examining the gene expression profiles in relation to hormone receptor status. Estrogen receptor positivity was present in 33% and progesterone receptor positivity in 84%. In a comparison of PR+ and PR− meningiomas, the study showed up-regulation of ten genes, and down-regulation of 14 genes. No genes separated ER+ from ER− meningiomas. As the number of candidate genes was small, no single pathways or groups of genes were clearly identified.
In 2009, Fèvre-Montange and colleagues [
25] published a transcriptomic study of 17 meningiomas (WHO grade I,
n = 10; WHO grade II,
n = 5; WHO grade III,
n = 2). As control tissue RNA from a human whole brain (72 years of age) was used. The aim was to distinguish between the different WHO grades and histopathological subtypes, and to identify factors predicating recurrence. Unsupervised cluster analysis showed three groups of samples: group A consisted of seven of ten grade I cases, group B of the remaining three grade I samples and all five grade II meningiomas, and finally group C consisted of the two grade III tumors. Statistical analysis revealed that 346 and 2,995 genes showed more than twofold over-expression in groups B and C, respectively. Similarly, 184 and 1,380 genes were down-regulated, respectively. Furthermore, the study showed differential gene expression between fibrous and meningothelial meningiomas, with 12 up-regulated and 20 down-regulated genes in the fibrous subset. Selected genes were validated with qRT-PCR.
The last published microarray study on meningiomas so far was published in 2009 and performed by Castells et al. [
26]. The aim was to assess whether automated categorization of brain tumors can be made by the use of microarray. Biopsies from 35 patients (17 glioblastomas and 18 meningothelial meningiomas) were subjected to cDNA-based microarray analysis. The study showed up to 100% prediction accuracy by using microarrays, thus providing evidence of possible clinical diagnostic use of this technology.