Hypermethylation and Transcriptional Downregulation of the <i>TIMP3</i> Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

Barski, Dimitri; Wolter, Marietta; Reifenberger, Guido; Riemenschneider, Markus J.

doi:10.1111/j.1750-3639.2009.00340.x

Cited by 75 publications

(69 citation statements)

References 26 publications

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“…Hypermethylation of the 22q12 gene TIMP3 and subse quent transcriptional downregulation (gene silencing) has been identified as a marker for an aggressive, high-grade meningioma phenotype. 4,49 Although there is some minor disagreement in the literature, Grade I tumors have been found to have significantly less aberrant methylation at TIMP3 than Grade II or III meningiomas.…”

Section: Tumor Suppressor Genesmentioning

confidence: 99%

A review of epigenetic and gene expression alterations associated with intracranial meningiomas

He¹,

Pham²,

Pease³

et al. 2013

FOC

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Object A more comprehensive understanding of the epigenetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide useful targets for molecular classification and development of targeted therapies for meningiomas. Methods The authors performed a review of the current literature to identify the epigenetic modifications associated with the formation and/or progression of meningiomas. Results Several epigenomic alterations, mainly pertaining to DNA methylation, have been associated with meningiomas. Hypermethylation of TIMP3 inactivates its tumor suppression activity while CDKN2 (p14[ARF]) and TP73 gene hypermethylation and HIST1H1c upregulation interact with the p53 regulation of cell cycle control. Other factors such as HOX, IGF, WNK2, and TGF-β epigenetic modifications allow either upregulation or downregulation of critical pathways for meningioma development, progression, and recurrence. Conclusions Genome-wide methylation profiling demonstrated that global hypomethylation correlates with tumor grades and severity. Identification of additional epigenetic changes, such as histone modification and higher-order chromosomal structure, may allow for a more thorough understanding of tumorigenesis and enable future individualized treatment strategies for meningiomas.

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Section: Tumor Suppressor Genesmentioning

confidence: 99%

A review of epigenetic and gene expression alterations associated with intracranial meningiomas

He¹,

Pham²,

Pease³

et al. 2013

FOC

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“…TIMP3 has been proposed as a tumor suppressor in several human cancer types. Silencing of TIMP3 through promoter hypermethylation has been associated with poor prognosis in a range of human cancers including kidney, brain, colon (Bachman et al, 1999), non-small cell lung (Zochbauer-Muller et al, 2001) and meningiomas (Barski et al, 2010). Loss of TIMP3 expression, through loss of heterozigosity on chromosome 22q, is frequently observed in various cancers, such as secondary glioblastoma (Nakamura et al, 2005) and clear renal cell carcinomas (Masson et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

et al. 2011

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Papillary thyroid carcinoma (PTC) arises from the thyroid follicular epithelium and represents the most frequent thyroid malignancy. PTC is associated with gene rearrangements generating RET/PTC and TRK oncogenes, and to the BRAFV600E activating point mutation. A role of tumor-suppressor genes in the pathogenesis of PTC has not been assessed yet. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene, encoding a metalloproteinases inhibitor and capable of inhibiting growth, angiogenesis, invasion and metastasis of several cancers, was found to be silenced by promoter methylation in a consistent fraction of PTCs, in association with tumor aggressiveness and BRAFV600E mutation, thus suggesting an oncosuppressor role. To explore this possibility, in this study we performed gene expression and functional studies. Analysis of gene expression data produced in our laboratory as well as meta-analysis of publicly available data sets confirmed the downregulation of TIMP3 gene expression in PTC with respect to normal thyroid. The functional consequences of TIMP3 downregulation were investigated in the PTC-derived NIM1 cell line, in which the expression of TIMP3 is silenced. Restoration of TIMP3 expression by exposure to soluble TIMP3 protein or by complementary DNA transfection had no effect on the growth rate of NIM1 cells. Instead, it affected the adhesive, migratory and invasive capabilities of NIM1 cells by modulating several proteins involved in these processes. A striking effect was observed in vivo, as TIMP3 reduced the tumorigenicity of NIM1 cells by repressing angiogenesis and macrophage infiltration. Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC.

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“…22 Research into altered methylation of genes related to meningioma has revealed hypermethylation of purported antiproliferation genes in atypical and anaplastic meningiomas. 17 Several reports have shown that underexpression through hypermethylation of the MGMT, 2 TIMP3, 3 and NDRG2 18 genes is associated with malignant potential or progression. A genome-wide methylation study described 3 clusters of methylation patterns based on comparing WHO Grade I and II meningiomas with normal meninges.…”

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confidence: 99%

Methylation markers of malignant potential in meningiomas

Vengoechea

Sloan

Chen³

et al. 2013

JNS

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Object Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have significant clinical value. This validated genome-wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas. Methods Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates. Results The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1). Conclusions A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas.

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Hypermethylation and Transcriptional Downregulation of the TIMP3 Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

Cited by 75 publications

References 26 publications

A review of epigenetic and gene expression alterations associated with intracranial meningiomas

A review of epigenetic and gene expression alterations associated with intracranial meningiomas

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

Methylation markers of malignant potential in meningiomas

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