Identification of Promoter Region Methylation Patterns of MGMT, CDKN2A, GSTP1, and THBS1 Genes in Intracranial Meningioma Patients

Aydemir, Fatih; Yurtçu, Erkan; Balci, Tugce B.; Şahin, Feride İffet; Gülşen, Salih; Altınörs, Nur

doi:10.1089/gtmb.2011.0245

Cited by 17 publications

(11 citation statements)

References 23 publications

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“…According to the two-hit model of Knudson, DNA methylation can be a second hit inactivating those tumor suppressors, following genetic mutations which are also often present in meningiomas in this locus (Boström et al 2001 ; Knudson 1996 ). Similar findings concerning DNA methylation in meningiomas were recently published by Aydemir et al ( 2012 ), who found p16INK4A to be methylated in 8.3 % [3/36] of cases and Liu et al ( 2005 ) reporting methylation of this gene in 10 % of samples. Amatya et al ( 2004 ) found methylation of p14ARF gene in 5 of 58 cases of benign meningiomas (8.6 %), 2 of 10 cases of atypical meningiomas (20 %), and 2 of 4 cases of anaplastic meningiomas (50 %).…”

Section: Discussionsupporting

confidence: 86%

DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade

Majchrzak‐Celińska

Paluszczak

Szalata

et al. 2015

J Cancer Res Clin Oncol

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PurposeAlthough meningiomas are common central nervous system tumors, the biomarkers allowing early diagnosis and progression are still needed. The aim of this study was to evaluate the methylation status of 12 cancer-related genes, namely ERCC1, hMLH1, ATM, CDKN2B (p15INK4B), p14ARF, CDKN2A (p16INK4A), RASSF1A, RUNX3, GATA6, NDRG2, PTEN, and RARβ, in 44 meningioma samples of WHO grade I and II.MethodsAll genes were analyzed using methylation-specific polymerase chain reaction, while pyrosequencing (PSQ) was used to study NDRG2 promoter methylation.ResultsThe most frequently methylated genes in both types of meningiomas were p14ARF, RASSF1A, and p15INK4B. RUNX3, GATA6, and p16INK4A were methylated to a lesser extent, whereas ATM and RARβ were found to be methylated in a marginal number of patients. The ERCC1, hMLH1, NDRG2, and PTEN genes were unmethylated in all cases. Although tumors of the same grade according to WHO criteria had different genes methylated, the number of methylated genes for each individual patient was low. RUNX3 methylation significantly correlated with meningioma WHO grade, therefore, can be considered as a potential indicator of tumor aggressiveness. The sequence of NDRG2 chosen for PSQ analysis was found methylated in the majority of meningiomas; however, the methylation level was only slightly elevated as compared to non-cancerous brain.ConclusionsOverall, the results of this study confirm that DNA methylation plays an important role in the pathogenesis of meningiomas. Further investigations, particularly concerning RUNX3 methylation, are necessary in order to assess the clinical usefulness of the methylation analysis of the studied genes.

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Section: Discussionsupporting

confidence: 86%

DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade

Majchrzak‐Celińska

Paluszczak

Szalata

et al. 2015

J Cancer Res Clin Oncol

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“…In the past, several studies focused on investigating promoter methylation mainly using a targeted approach for a limited number of genes [4,6–8,11,30,14,15,34,38,47]. With time, molecular advances allowed interrogation at a larger number of CpG loci [35] culminating with the methylation assays from Illumina (27k and 450k) interrogating approximately 27.000 and 450.000 CpG loci [74,21].…”

Section: Discussionmentioning

confidence: 99%

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Olar

Wani

Wilson³

et al. 2017

Acta Neuropathol

157

118

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Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n=140) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised modeling on a training set (n=89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNA)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p=0.0793). The methylation predictor however was significantly associated with tumor recurrence (p<0.0001). CNA were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.

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“…In a similar way, Goutagny et al [ 34 ] have recently shown by SNP-arrays that the most frequent genomic alteration of meningiomas upon progression to grade III was loss of CDKN2A / CDKN2B . Additionally, inactivation through hypermethylation of CpG islands has also been reported in a smaller proportion of meningiomas, including hypermethylation of CDKN2A/p16 INKa in 8-17% of cases, CDKN2A/p14 ARF in 4-13%, and CDKN2B/p15 ARF in 4% of these tumors [ 17 , 35 ]. All such correlations also appear to have a prognostic impact since meningiomas with 9p21 losses have a significantly shorter survival and a worse clinical outcome than cases showing no alterations of chromosome 9p21 [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic/molecular alterations of meningiomas and the signaling pathways targeted

et al. 2015

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Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features.

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Identification of Promoter Region Methylation Patterns of MGMT, CDKN2A, GSTP1, and THBS1 Genes in Intracranial Meningioma Patients

Cited by 17 publications

References 23 publications

DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade

DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Genetic/molecular alterations of meningiomas and the signaling pathways targeted

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