Glycation Interferes with the Expression of Sialyltransferases in Meningiomas.

Meningiomas are the most common non-malignant intracranial tumors and prefer, like most tumors, anaerobic glycolysis for energy production (Warburg effect). This anaerobic glycolysis leads to an increased synthesis of the metabolite methylglyoxal (MGO) or glyoxal (GO), which is known to react with amino groups of proteins. This reaction is called glycation, thereby building advanced glycation end products (AGEs). In this study, we investigated the influence of glycation on sialylation in two meningioma cell lines, representing the WHO grade I (BEN-MEN-1) and the WHO grade III (IOMM-Lee). In the benign meningioma cell line, glycation led to differences in expression of sialyltransferases (ST3GAL1/2/3/5/6, ST6GAL1/2, ST6GALNAC2/6, and ST8SIA1/2), which are known to play a role in tumor progression. We could show that glycation of BEN-MEN-1 cells led to decreased expression of ST3Gal5. This resulted in decreased synthesis of the ganglioside GM3, the product of ST3Gal5. In the malignant meningioma cell line, we observed changes in expression of sialyltransferases (ST3GAL1/2/3, ST6GALNAC5, and ST8SIA1) after glycation, which correlates with less aggressive behavior.

Distinct Expression Patterns of Carbonic Anhydrase IX in Clear Cell, Microcystic, and Angiomatous Meningiomas.

Clear cell, microcytic, and angiomatous meningiomas are 3 vasculature-rich variants with overlapping morphological features but different prognostic and treatment implications. Distinction between them is not always straightforward. We compared the expression patterns of the hypoxia marker carbonic anhydrase IX (CA-IX) in meningiomas with predominant clear cell (n = 15), microcystic (n = 9), or angiomatous (n = 11) morphologies, as well as 117 cases of other World Health Organization recognized histological meningioma variants. Immunostaining for SMARCE1 protein, whose loss-of-function has been associated with clear cell meningiomas, was performed on all clear cell meningiomas, and selected variants of meningiomas as controls. All clear cell meningiomas showed absence of CA-IX expression and loss of nuclear SMARCE1 expression. All microcystic and angiomatous meningiomas showed diffuse CA-IX immunoreactivity and retained nuclear SMARCE1 expression. In other meningioma variants, CA-IX was expressed in a hypoxia-restricted pattern and was highly associated with atypical features such as necrosis, small cell change, and focal clear cell change. In conclusion, CA-IX may serve as a useful diagnostic marker in differentiating clear cell, microcystic, and angiomatous meningiomas.

Correlations between the expression of hTERT and α and ß splice variants in human brain tumors.

BACKGROUND: Astrocytomas are diffusible infiltrative and aggressive brain tumors that are extensive and heterogeneous clusters of neoplastic growths in the central nervous system (CNS). Meningioma tumors are commonly benign but may demonstrate an invasive pattern with frequent recurrences. Human telomerase reverse transcriptase (hTERT) is an unfavorable prognostic factor for several types of cancers, and there are controversies about its role. OBJECTIVES: In the present study, we investigated the relative expression of hTERT splice variants in 2 groups of brain tumors compared to non-tumor samples. MATERIAL AND METHODS: The mRNA of 40 brain tumor samples and 4 control samples was extracted; mRNA expression of hTERT α-deletion and ß-deletion variants, as well as the wild type isoform, was quantified using quantitative reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: The α-deletion variant was significantly expressed in primary benign meningeal tumors (p = 0.01). The results indicate a positive correlation between the relative expression of hTERT mRNA transcript and α-deletion and ß-deletion variants in both groups of tumors (meningiomas and astrocytomas). A strong association between the expression of the full-length splice variant and the ß-deletion variant was observed in astrocytoma tumors (p = 0.045). The most significant correlations were found between the hTERT full-length and ß-deletion variants in high-grade meningiomas (p = 0.018, correlation coefficient (CC) = 0.964) and grade II astrocytomas (p = 0.015; CC = 0.580). In addition, in low grades of both types of tumors, the hTERT full-length variant and especially the α-deletion variant were the predominant isoforms. The overexpression of hTERT and ß-deletion variants in high grades of these tumors was statistically significant. Our findings indicate that α-deletion and ß-deletion isoforms are associated with high levels of full-length hTERT mRNA in both groups of brain tumor patients. CONCLUSIONS: Changes in the splicing pattern of hTERT splice variants in brain tumors and their correlation with pathological alterations in cells could be applied as diagnostic or prognostic biomarkers, or possibly as targets for cancer therapy. However, the function and biological role of hTERT splice variants remain to be clarified.

A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas.

Meningiomas are the most common primary intracranial adult tumor. All Neurofibromatosis 2 (NF2)-associated meningiomas and ~60% of sporadic meningiomas show loss of NF2 tumor suppressor protein. There are no effective medical therapies for progressive and recurrent meningiomas. Our previous work demonstrated aberrant activation of mTORC1 signaling that led to ongoing clinical trials with rapamycin analogs for NF2 and sporadic meningioma patients. Here we performed a high-throughput kinome screen to identify kinases responsible for mTORC1 pathway activation in NF2-deficient meningioma cells. Among the emerging top candidates were the mTORC2-specific target serum/glucocorticoid-regulated kinase 1 (SGK1) and p21-activated kinase 1 (PAK1). In NF2-deficient meningioma cells, inhibition of SGK1 rescues mTORC1 activation, and SGK1 activation is sensitive to dual mTORC1/2 inhibitor AZD2014, but not to rapamycin. PAK1 inhibition also leads to attenuated mTORC1 but not mTORC2 signaling, suggesting that mTORC2/SGK1 and Rac1/PAK1 pathways are independently responsible for mTORC1 activation in NF2-deficient meningiomas. Using CRISPR-Cas9 genome editing, we generated isogenic human arachnoidal cell lines (ACs), the origin cell type for meningiomas, expressing or lacking NF2. NF2-null CRISPR ACs recapitulate the signaling of NF2-deficient meningioma cells. Interestingly, we observe increased SGK1 transcription and protein expression in NF2-CRISPR ACs and in primary NF2-negative meningioma lines. Moreover, we demonstrate that the dual mTORC1/mTORC2 inhibitor, AZD2014 is superior to rapamycin and PAK inhibitor FRAX597 in blocking proliferation of meningioma cells. Importantly, AZD2014 is currently in use in several clinical trials of cancer. Therefore, we believe that AZD2014 may provide therapeutic advantage over rapalogs for recurrent and progressive meningiomas.

The mTOR signaling pathway as a treatment target for intracranial neoplasms.

Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has become an attractive target for human cancer therapy. Hyperactivation of mTOR has been reported in both sporadic and syndromic (hereditary) brain tumors. In contrast to the large number of successful clinical trials employing mTOR inhibitors in different types of epithelial neoplasms, their use to treat intracranial neoplasms is more limited. In this review, we summarize the role of mTOR activation in brain tumor pathogenesis and growth relevant to new human brain tumor trials currently under way using mTOR inhibitors.

Transglutaminase 2 expression is increased as a function of malignancy grade and negatively regulates cell growth in meningioma.

Most meningiomas are benign, but some clinical-aggressive tumors exhibit brain invasion and cannot be resected without significant complications. To identify molecular markers for these clinically-aggressive meningiomas, we performed microarray analyses on 24 primary cultures from 21 meningiomas and 3 arachnoid membranes. Using this approach, increased transglutaminase 2 (TGM2) expression was observed, which was subsequently validated in an independent set of 82 meningiomas by immunohistochemistry. Importantly, the TGM2 expression level was associated with increasing WHO malignancy grade as well as meningioma recurrence. Inhibition of TGM2 function by siRNA or cystamine induced meningioma cell death, which was associated with reduced AKT phosphorylation and caspase-3 activation. Collectively, these findings suggest that TGM2 expression increases as a function of malignancy grade and tumor recurrence and that inhibition of TGM2 reduces meningioma cell growth.

Immunohistochemical analysis of cyclooxygenase-2 and brain fatty acid binding protein expression in grades I-II meningiomas: correlation with tumor grade and clinical outcome after radiotherapy.

This study was done to evaluate the association of cyclooxygenase 2 (COX-2) and brain fatty acid binding protein (BFABP) with tumor grade and outcome of grades I-II meningiomas treated with radiotherapy. From 1996 to 2008, 40 patients with intracranial grades I-II meningiomas were treated with radiotherapy. Immunohistochemical staining for COX-2 and BFABP were performed on formalin-fixed paraffin-embedded tissues. COX-2 expression was significantly associated with BFABP status and both COX-2 (P < 0.01) and BFABP (P = 0.01) expression were stronger in the grade II meningiomas than in grade I tumors. Among the clinicopathologic factors, age and COX-2 status were prognostic in progression-free survival. Patients with moderate or strong COX-2 expression had worse outcome than those with negative or weak COX-2 expression (P = 0.03) after controlling for potential confounders. Our results suggest that the molecular biomarker COX-2 has prognostic significance in intracranial grades I-II meningiomas following radiotherapy.

Pathodiagnostic parameters and evaluation of O6- methyl guanine methyl transferase gene promoter methylation in meningiomas.

Histopathological evaluation and grading of meningioma give important prognostic information. We evaluated retrospectively monotonous sheeting, necrosis, hypercellularity, nuclear pleomorphism, small cell changes, brain invasion, mitosis, mast cells, psammoma bodies, MIB-1 labeling index (MIB-1 LI) and histological grade of 230 primary meningioma tumors according to the latest World Health Organization (WHO) classification. To reveal any possible association between clinical features and promoter hypermethylation of O(6)-methylguanine-DNA methyltransferase (MGMT) as an important epigenetic modification in many human cancers, we also evaluated the methylation status of MGMT in meningiomas by a SYBR-green-based real-time PCR method. There was a female predominance (2.38 to 1) in the meningiomas. The mean age of the patients was 49.9 ± 12.6 years (range 16 to 78 years). Transitional meningiomas were the most common subtype of the meningiomas (35.21%, n=81). Most of the meningiomas were located in the falx and parasagital area. There was a significant correlation between histopathological features of malignancy. These features were observed more frequently and with statistical relation to grade II rather than grade I. Mast cells, psammoma bodies and nuclear pleomorphism had poor associations (P>0.05). When we re-evaluated the tumor grading, 31 patients with grade I meningiomas were upgraded to grade II. None of the meningiomas tested by MSQP were methylated in MGMT promoter sequence. High MIB-1 LI could be indicative for higher grade of meningioma. Continuous revision of the classification system is needed to improve the accuracy of prognostic judgments in meningioma. The data confirm that there is no rationale to test meningiomas for MGMT methylation status.

Clinicopathological evaluation of cyclooxygenase-2 expression in meningioma: immunohistochemical analysis of 76 cases of low and high-grade meningioma.

Tumorigenic activity of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the production of prostaglandins (PGs), has been proved for some types of cancer, including brain tumors. We evaluated expression of COX-2 in meningioma, one of the most common intracranial tumors in adults which accounts for 24-30 % of intracranial tumors. We performed immunostaining for COX-2 in 76 cases of meningioma consisting of 44 cases of low-grade (WHO Grade I) and 32 cases of high-grade (29 cases of Grade II and 3 cases of Grade III) meningioma, and evaluated COX-2 expression levels on the basis of staining intensity and proportion in tumor cells. The expression level of COX-2 in meningioma cells was significantly correlated with WHO grade (P = 0.0153). In addition, COX-2 expression was significantly correlated with MIB-1 labeling index for all 76 cases of meningioma (P = 0.0075), suggesting tumor promotion by COX-2 in meningioma progression. Our results may indicate the therapeutic value of non-steroidal anti-inflammatory drugs against meningioma, especially for patients with elevated proliferation, to regulate the tumorigenic activity of COX-2 in meningioma cells.

Expression of MMP-2 and MMP-9 in benign canine rostrotentorial meningiomas is not correlated to the extent of peritumoral edema.

Matrix metalloproteinases (MMPs) are proteolytic enzymes involved with extracellular matrix degradation. They have been considered to be important for tumor growth and development of peritumoral edema. This retrospective study investigated the expression of MMP subtypes 9 and 2 in canine intracranial meningiomas and their association with peritumoral edema. Twenty-two cases of histologically confirmed grade I meningiomas based on human World Health Organization classification were enrolled. Tumor volume and peritumoral edema were measured by magnetic resonance imaging volumetry. The intratumoral MMP expression was semiquantitatively assessed by immunoreactivity scores and compared with the imaging data. MMP-9 was expressed in all the samples (22/22), whereas proMMP-2 was expressed in 21 of 22 meningiomas, and a/proMMP-2 was expressed in 9 of 22. The immunoreactivity scores were not statistically linked to the severity of peritumoral edema. None of the evaluated MMP expression parameters were statistically linked to the edema index. Although both edema index and MMP-9 expression were highest in meningiomas of the olfactory and frontal region, only the latter mounted up to statistical significance (P = .002) if compared with parafalx and convexity meningiomas of the parietal lobe. In summary, MMP-2 and MMP-9 expression by tumor cells, evaluated through immunohistochemistry, is not predictive of the formation of peritumoral edema in canine rostrotentorial meningiomas.

Telomerase activity in human brain tumors: astrocytoma and meningioma.

Somatic cells do not have telomerase activity but immortalized cell lines and more than 85 % of the cancer cells show telomerase activation to prevent the telomere from progressive shortening. The activation of this enzyme has been found in a variety of human tumors and tumor-derived cell lines, but only few studies on telomerase activity in human brain tumors have been reported. Here, we evaluated telomerase activity in different grades of human astrocytoma and meningioma brain tumors. In this study, assay for telomerase activity performed on 50 eligible cases consisted of 26 meningioma, 24 astrocytoma according to the standard protocols. In the brain tissues, telomerase activity was positive in 39 (65 %) of 50 patients. One sample t test showed that the telomerase activity in meningioma and astrocytoma tumors was significantly positive entirely (P < 0.001). Also, grade I of meningioma and low grades of astrocytoma (grades I and II) significantly showed telomerase activity. According to our results, we suggest that activation of telomerase is an event that starts mostly at low grades of brain including meningioma and astrocytoma tumors.

In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1.

Expression and activity of indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting step of the kynurenine pathway of tryptophan catabolism, can enable tumor cells to effectively evade the host's immune response. The potential role of this system was investigated in meningiomas. Surgical specimens from 22 patients with meningiomas were used for cellular, immunological and molecular techniques (immunofluorescence, western blotting, RT-PCR and biochemical assay of enzyme activity) to investigate the expression and activity of IDO. In addition, PET imaging was obtained preoperatively in 10 patients using the tracer α-[ ( 11) C]methyl-L-tryptophan (AMT) which interrogates the uptake and metabolism of tryptophan. Strong AMT accumulation was noted in all meningiomas by PET imaging indicating in vivo tryptophan uptake. Freshly-resected meningiomas expressed both LAT1, the tryptophan transporter system and IDO, demonstrating an active kynurenine pathway. Dissociated meningioma cells lost IDO expression. Following exposure to interferon-γ (IFNγ), IDO expression was reinduced and could be blocked by a selective IDO1 inhibitor. IDO activity may represent an element of local self-protection by meningiomas and could be targeted by emerging IDO1 inhibitors.

Mast cells evaluation in meningioma of various grades.

Meningioma is a heterogenous group of primary brain tumors. The progression or recurrence is relatively very common; however, prognostic factors which may indicate those events are not known. The aim of the study was to evaluate the presence of mast cells within the low grade and high grade meningiomas. The material included 70 cases of meningomas (63 G1 grade cases) of adult subjects (range 23-84 years). In paraffin sections presence of tryptase, a marker of mast cells, was detected by immunohistochemistry in 10 random fields in each slide under the light microscope. The presence of the peritumoral oedema was estimated by brain computer tomography. The expression of tryptase was observed in 32% of low grade meningiomas and 86% of high grade meningiomas. The immunostained cells were observed close to the blood vessels. We conclude that the number of mast cells might be a significant prognostic factor for the recurrence or bad prognosis of meningiomas.

Fatty acid synthase is a predictive marker for aggressiveness in meningiomas.

Meningiomas are the most frequent intracranial tumors. Although most are benign WHO grade I tumors, grade II and III tumors are aggressive and survival is poor. Treatment options for grade II and III meningiomas are limited, and molecular targets are few. The re-programming of metabolic pathways including glycolysis, lipogenesis, and nucleotide synthesis is a hallmark of the physiological changes in cancer cells. Because fatty acid synthase (FAS), the enzyme responsible for the de-novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers, we investigated its involvement in meningiomas. We subjected 92 paraffin-embedded samples from 57 patients with grade I, 18 with grade II and III, and six with radiation-induced tumors to immunohistochemical study of FAS. Whereas its expression was increased in grade II and III meningiomas (62.9 %) compared with grade I tumors (29.8 %) (chi-squared test: p < 0.001), FAS was expressed in grade I tumors with a high MIB-1 index and infiltration into surrounded tissues. All radiation-induced meningiomas expressed FAS and its expression was positively correlated with the MIB-1 index (p < 0.005). Our findings suggest that increased FAS expression reflects the aggressiveness of meningiomas and that it may be a novel therapeutic target for treatment of unresectable or malignant tumors.

Possible role of matrix metalloproteinases (MMPs) in hyperostosis of intracranial meningiomas.

OBJECT: Although bone invasion and hyperostosis are common phenomena in patients with intracranial meningiomas, the basic pathomechanism is not fully understood. Based on an immunohistochemical study of surgically resected samples with hyperostosis, we postulate a possible mechanism of hyperostosis in patients with intracranial meningiomas. MATERIALS AND METHODS: Forty-six meningiomas were evaluated in this study. Twenty-six meningiomas associated with hyperostosis specimens served as the study group, and 20 meningiomas without any bony changes served as controls. An immunohistochemical staining technique was used to detect the expression of matrix metalloproteinase (MMP)-2, -9, and -13, membrane type (MT)1-MMP, estrogen receptor (ER), and progesterone receptor (PR) in the main tumor and hyperostotic portions of the studied samples. RESULTS: In the non-hyperostosis group, expression of MMP-13, MT1-MMP, and ER was significantly less than in the main tumor portion of hyperostotic meningiomas, while there was no difference in the expression of MMP-2 and -9 and PR in the main tumor between the two groups. In the hyperostosis group, the immunoreactivity of MMP-2 in the hyperostotic portion revealed a higher pattern of expression than the main tumor (p < 0.002). The expression of MMP-9, MT1-MMP, ER, and PR had relatively positive immunoreactivity in the main tumor portion (P < 0.05). CONCLUSIONS: Increased expression of MMP-13 and MT1-MMP in the tumor portion of hyperostosis of meningiomas might contribute to the initiation of osteolysis. Activated MMP-2 in hyperostotic lesions may change the physiological metabolism of the skull bone, thus playing an important role in hyperostosis formation.

Susceptibility to 5-aminolevulinic acid based photodynamic therapy in WHO I meningioma cells corresponds to ferrochelatase activity.

5-Aminolevulinic acid (5-ALA) is a natural precursor of protoporphyrin IX (PpIX), which can be used as a photosensitizer in photodynamic therapy (PDT). Accumulation of PpIX in benign meningioma cells has been observed previously, its exploitation for PDT, however, was discouraged by inconsistent results. To evaluate PDT for benign meningiomas, we investigated PpIX synthesis in two human meningioma cell lines (HBL-52 and BEN-MEN-1), their respective extracellular loss of PpIX and corresponding ferrochelatase (FECH) activity as well as their susceptibility to PDT. We demonstrated PpIX production after 5-ALA administration and minor loss to the extracellular space in both cell lines. However, significantly more (up to five times) PpIX was accumulated in BEN-MEN-1 as compared with HBL-52 cells. FECH activity was 2.7-fold higher in HBL-52 compared with BEN-MEN-1 cells and accordingly higher FECH levels could be shown in HBL-52 cells by Western blot analysis. BEN-MEN-1 cells were much more sensitive to PDT and cells could be almost completely killed by irradiation doses of 2 J cm(-2) , whereas HBL-52 showed only an insufficient response at this irradiation dose. We conclude that differences in intracellular PpIX concentrations between HBL-52 and BEN-MEN-1 benign meningioma cells were mainly due to differences in FECH activity and that these differences correspond to their susceptibility to 5-ALA-induced PDT.

MMP-9 expression in meningiomas: a prognostic marker for recurrence risk?

Despite total macroscopic resection of meningiomas relapses do occur in these tumours, possibly because of microscopic clusters of neoplastic cells left in the dura mater or in the arachnoid membrane. The invasiveness of the neoplastic cells of human meningiomas has been related to expression of matrix-metalloproteinase-9 (MMP-9), a peptidase actively implicated in the degradation of the extracellular matrix; nonetheless, the prognostic value of MMP-9 in the risk of recurrence of meningiomas has not been sufficiently investigated. Herein, we analysed MMP-9 expression in a series of meningiomas of different histotype and histological grade and assessed its correlation with various clinico-pathological indicators and with the clinical outcome of these tumours. We also tested the eventual pro-angiogenic role of MMP-9 expression in meningiomas through its correlation with vascular endothelial growth factor (VEGF) and microvessel density (MVD) revealed in the same cases. MMP-9 expression was observed in 64% of cases; high expression of this protein was significantly associated with high histological grade and proliferation index, but not with high MVD, of the tumours. A trend towards correlation between MMP-9 and VEGF expression was found, although statistical significance was not reached. In addition, high MMP-9 expression was a negative independent prognostic factor associated with higher recurrence risk in totally resected meningiomas. In conclusion, we demonstrated for the first time the potential prognostic value of MMP-9 expression in meningiomas. Inhibition of MMP-9 may be a new therapeutic strategy to prevent recurrences of meningiomas, particularly the high-grade type.

Differential expression of type 2 3α/type 5 17ß-hydroxysteroid dehydrogenase (AKR1C3) in tumors of the central nervous system.

Human aldo-keto reductase (AKR) 1C3, type 2 3α-hydroxysteroid dehydrogenase (HSC)/ type 5 17ß-HSD, is known to be involved in steroids, prostaglandins, and lipid aldehydes metabolism. The expression of AKR1C3 has been demonstrated in hormone-dependent normal tissues such as breast, endometrium, prostate, and testis; and de -regulated AKR1C3 expression has been shown in breast carcinoma, endometrial hyperplasia, endometrial carcinoma, and prostate carcinoma. AKR1C3 expression has also been demonstrated in hormone-independent normal tissues (renal tubules and urothelium) and neoplastic tissues (renal cell carcinoma, Wilm's tumor, and urothelial cell carcinoma). Extensive expression of AKR1C3 in normal and neoplastic as well as hormone-dependent and hormone-independent tissues indicates that AKR1C3 may have functions beyond steroid hormone metabolism. In this report, we describe a widespread expression of AKR1C3 in glial neoplasms and meningiomas, with limited expression in medulloblastoma and no expression in Schwannoma. These tumors, except meningioma, are not classically considered to be sex hormone-dependent or related brain tumors. The current results corroborate our earlier observations that AKR1C3 is expressed in both sex hormone-dependent and hormone-independent malignancies. Similar to AKR1C3 distribution in Wilm's tumor, we also demonstrate that expression of AKR1C3 is reduced in tumors with embryonic phenotypes.

Two common nonsynonymous paraoxonase 1 (PON1) gene polymorphisms and brain astrocytoma and meningioma.

BACKGROUND: Human serum paraoxonase 1 (PON1) plays a major role in the metabolism of several organophosphorus compounds. The enzyme is encoded by the polymorphic gene PON1, located on chromosome 7q21.3. Aiming to identify genetic variations related to the risk of developing brain tumors, we investigated the putative association between common nonsynonymous PON1 polymorphisms and the risk of developing astrocytoma and meningioma. METHODS: Seventy one consecutive patients with brain tumors (43 with astrocytoma grade II/III and 28 with meningioma) with ages ranging 21 to 76 years, and 220 healthy controls subjects were analyzed for the frequency of the nonsynonymous PON1 genotypes L55M rs854560 and Q192R rs662. All participants were adult Caucasian individuals recruited in the central area of Spain. RESULTS: The frequencies of the PON1 genotypes and allelic variants of the polymorphisms PON1 L55M and PON1 Q192R did not differ significantly between patients with astrocytoma and meningioma and controls. The minor allele frequencies were as follows: PON1 55L, 0.398, 0.328 and 0.286 for patients with astrocytoma, meningioma and control individuals, respectively; PON1 192R, 0.341, 0.362 and 0.302 for patients with astrocytoma, meningioma and control individuals, respectively. Correction for age, gender, or education, made no difference in odds ratios and the p values remained non-significant. Haplotype association analyses did not identify any significant association with the risk of developing astrocytoma or meningioma. CONCLUSIONS: Common nonsynonymous PON1 polymorphisms are not related with the risk of developing astrocytoma and meningioma.